JP2010507674A - Tricyclic compounds as matrix metalloprotease inhibitors - Google Patents

Abstract

The present invention provides compounds of formula I:

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X and Y are as defined herein, and a pharmaceutically acceptable salt, hydrate or ester thereof That's right. The present teachings also provide methods for preparing compounds of formula I and methods for treating pathological conditions or disorders mediated in whole or in part by matrix metalloproteases (eg, asthma and chronic obstructive pulmonary disease). However, the method includes the step of administering a therapeutically effective amount of a compound of Formula I to a mammal (eg, a human) in need of such treatment.

Description

Introduction The present teachings relate to tricyclic compounds and derivatives that can be used to inhibit matrix metalloproteases. The present teachings also relate to methods for preparing the tricyclic compounds and derivatives and methods of using them.

  Matrix metalloproteases (MMPs) are a family of over 20 zinc-dependent proteases that have the ability to degrade extracellular matrix (ECM) components that are associated with both normal tissue remodeling and destruction. Due to the degradable nature of these enzymes, the expression and activity of MMPs is highly regulated, and when MMP control is clearly lost, pathological destruction of connective tissue and subsequent disease states are also lost. Can be done. For example, disruption of the balance between MMPs and tissue metalloproteinase inhibitors (TIMPs) that control the activity of MMPs can lead to rheumatoid arthritis and osteoarthritis, atherosclerosis, heart failure, fibrosis, emphysema and tumor growth. Observed in pathologies such as invasion and metastasis. Therefore, MMP is a very effective target for the design of therapeutics, especially for disease areas of arthritis and oncology (for review see, for example, Non-Patent Document 1; and Non-Patent Document 2).

  MMP is broadly classified as collagenase (MMP-1, MMP-8 and MMP-13), gelatinase (MMP-2 and MMP-9), stromelysin (MMP-3, MMP-10 and MMP-11), elastase. (MMP-7 and MMP-12) and membrane-bound MMPs (MMP-14 to MMP-25). Among these classes, gelatinase has been shown to be the MMP most associated with tumor growth and spread, and collagenase is related to the pathogenesis of arthritis. For example, see Non-Patent Document 3; Non-Patent Document 4; Non-Patent Document 5; Non-Patent Document 6; In addition, there is evidence to suggest that gelatinase is involved in plaque failure associated with atherosclerosis. For example, see Non-Patent Document 9; and Non-Patent Document 10. MMP is restenosis, MMP-mediated osteopenia, central nervous system inflammatory disease, skin aging, septic arthritis, corneal ulcer, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, traumatic Degeneration of cartilage after joint injury, demyelinating disease of the nervous system, liver cirrhosis, colitis, glomerular disease of the kidney, early rupture of the fetal membrane, inflammatory bowel disease, periodontal disease, age-related macular degeneration , Diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumor, ocular neovascularization / neovascularization and corneal graft rejection It is also associated with various other diseases.

  Like many MMPs, MMP-12, a macrophage metalloelastase, can degrade many ECM components. Studies with various disease animal models provided evidence that MMP-12 is an important mediator of various diseases. For example, studies conducted to examine the involvement of macrophages in rheumatoid arthritis showed high levels of MMP-12 expression in synovial tissue and synovial fluid from patients with rheumatoid arthritis compared to patients with osteoarthritis Was observed. See Non-Patent Document 11. Other studies have associated MMP-12 with increased atherosclerotic lesion instability. For example, see Non-Patent Document 12. It was also suggested that MMP-12 expression may function as a prognostic indicator for early tumor recurrence. See Non-Patent Document 13.

  Asthma and chronic obstructive pulmonary disease (COPD) are both chronic lung diseases characterized by the accumulation of inflammatory cells, airflow obstruction and airway remodeling. MMPs are associated with a major class of proteolytic enzymes that induce airway remodeling. For example, see Non-Patent Document 14. In particular, MMP-12 has been demonstrated to play an important role in airway inflammation and remodeling. In recent studies, for example, by immunohistochemistry, bronchoalveolar lavage (BAL) cells from patients with moderate to severe COPD and bronchopulmonary biopsies showed higher MMP-12 expression than controls. Indicated. See Non-Patent Document 15. Similarly, other studies have demonstrated that induced sputum from patients with mild to moderate COPD has higher expression and enzymatic activity of MMP-12 compared to nonsmokers, smokers or smokers It was done. See Non-Patent Document 16.

  Accordingly, MMP inhibitors, particularly MMP-12 inhibitors, may be therapeutically beneficial for treating various pathological conditions and / or disorders.

Woessner, J .; F. (1991), FASEB J. et al. , 5: 2145-2154 Coussens, L.C. M.M. (2002), Science, 295 (5564): 2387-2392. Ellenrieder, V.M. (2000), Int. J. et al. Cancer, 85 (1): 14-20 Singer, C.I. F. (2002), Breast Cancer Res. Treat. , 72 (1): 69-77 Nikcola, J. et al. (2005), Clin. Cancer Res. 11: 5158-5166 Lubbe, W. et al. J. et al. (2006), Clin. Cancer Res. 12: 1876-1882 Dean, D.D. D. (1991), Sem. Arthritis Rheum. , 20 (6 Suppl 2): 2-11 Jackson, C.D. (2001), Inflamm. Res. , 50: 183-186 Dolly, C.I. M.M. (1995), Cir. Res. , 77: 863-868 Kuzuya, M .; (2006), Arterioscler. Thromb. Vasc. Biol. , 26 (5): 1120-1125 Liu, M .; (2004), Arthritis & Rheumatism, 50 (10): 3112-3117. Johnson, J.M. L. (2005), PNAS, 102 (43): 15575-15580. Hofmann H.M. S. (2005), Clin. Cancer Res. , 11 (3): 1086-1092 Suzuki, R.A. Y. (2004), Treat. Respir. Med. , 3: 17-27 Molet, S.M. (2005), Inflamm. Res. , 54 (1): 31-36 Demedts, I.D. K. (2006), Thorax, 61: 196-201.

SUMMARY The present teachings provide formula I:

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X and Y are defined herein in relation to the compounds of, and pharmaceutically acceptable salts, hydrates and esters thereof It is as follows.

  The present teachings also provide methods of preparing compounds of formula I and methods of treating pathological conditions or disorders mediated in whole or in part by matrix metalloproteases (eg, asthma and chronic obstructive pulmonary disease). Provided, the methods include administering to a patient, eg, a patient in need of such treatment, a therapeutically effective amount of a compound of formula I.

DETAILED DESCRIPTION In one aspect, the present teachings are of formula I:

(Where:
R ¹ is an N-linked, free carboxyl or carboxyl-protected, natural or non-natural amino acid, or N-linked amino acid derivative;
R ² and R ³ are independently a) H, b) oxo, c) —OR ⁸ , d) —S (O) _m R ⁸ , e) —S (O) _m OR ⁸ , f) — _{^{S (O) m NR 8 R}} 9, g) -C (O) R 8, h) -C (O) OR 8, i) -C (O) NR 8 R 9, j) -C (S) OR ⁸ , k) -C (S) R ⁸ , 1) -C (S) NR ⁸ R ⁹ , m) -C (NR ⁸ ) NR ⁸ R ⁹ , n) C _1-10 alkyl group, o) C _{2 -10} alkenyl group, p) C _2-10 alkynyl group, q) C _1-10 haloalkyl group, r) C _3-10 cycloalkyl group, s) C _6-14 aryl group, t) 3-14 membered cyclo a heteroalkyl group, or u) 5 to 13 membered heteroaryl group, wherein, n) each ~u) is substituted with 1-4 ^{-Z-R 10} group optionally; or The ^{R 2} and ^{R 3,} together with their common nitrogen ^{atom, a) -N = CR 7 R} 7, b) - N = O, c) -N = N-R 8, d) Forms a 3-14 membered cycloheteroalkyl group or e) a 5-13 membered heteroaryl group, wherein each of d) and e) is optionally substituted with 1-4 -ZR ¹⁰ Substituted with a group;
R ⁴ and R ⁵ are independently a) H, b) —CN, c) —NO ₂ , d) halogen, e) —OR ⁸ , f) —NR ⁸ R ⁹ , g) —S (O _{^{) m R 8, h) -S}} (O) m OR 8, i) -C (O) R 8, j) -C (O) OR 8, k) -C (O) NR 8 R 9, l) ^{-C (S) R 8, m} ) -C (S) OR 8, n) -C (S) NR 8 R 9, o) C 1-10 alkyl _{group, p) C 2-10} alkenyl group, q) C _2-10 alkynyl group, r) C _1-10 haloalkyl group, s) C _3-10 cycloalkyl group, t) C _6-14 aryl group, u) 3-14 membered cycloheteroalkyl group or v) 5 A 13-membered heteroaryl group, wherein each of o) to v) is optionally substituted with 1 to 4 -ZR ¹⁰ groups;
R ⁶ is a) H, b) -S (O) _m R ⁸ , c) -S (O) _m OR ⁸ , d) -C (O) R ⁸ , e) -C (O) OR ⁸ , ^{f) -C (O) NR 8} R 9, g) -C (S) R 8, h) -C (S) OR 8, i) -C (S) NR 8 R 9, j) C 1-10 An alkyl group, k) a C _2-10 alkenyl group, 1) a C _2-10 alkynyl group or m) a C _1-10 haloalkyl group, wherein each of j) -m) is optionally C ₆ Substituted with a _-14 aryl group or a 5-13 membered heteroaryl group, wherein each of the C _6-14 aryl group and the 5-13 membered heteroaryl group is optionally substituted with 1-4 -Z Substituted with -R ¹⁰ groups;
R ⁷ is in each occurrence a) H, b) —CN, c) —NO ₂ , d) halogen, e) oxo, f) —OR ⁸ , g) —NR ⁸ R ⁹ , h) —N. _{^{(O) R 8 R 9,}} i) -S (O) m R 8, j) -S (O) m O-R 8, k) -S (O) m NR 8 R 9, l) -C ( ^{O) R 8, m) -C} (O) OR 8, n) -C (O) NR 8 R 9, o) -C (S) R 8, p) -C (S) OR 8, q) - C (S) NR ⁸ R ⁹ , r) -Si (C _1-10 alkyl) ₃ , s) C _1-10 alkyl group, t) C _2-10 alkenyl group, u) C _2-10 alkynyl group, v ) C _1-10 haloalkyl group, w) C _3-10 cycloalkyl group, x) C _6-14 aryl group, y) 3-14 membered cycloheteroalkyl group or z) 5-13 membered heteroary. Wherein each of r) to z) is optionally substituted with 1 to 4 -ZR ¹⁰ groups;
R ⁸ and R ⁹ are independently in each occurrence a) H, b) —OR ¹¹ , c) —SR ¹¹ , d) —S (O) _m R ¹¹ , e) —S (O) _{^{m -OR 11, f) -S (}} O) m -NR 11 R 12, g) -C (O) R 11, h) -C (O) OR 11, i) -C (O) NR 11 R 12 J) —C (S) NR ¹¹ R ¹² , k) C _1-10 alkyl group, 1) C _2-10 alkenyl group, m) C _2-10 alkynyl group, n) C _1-10 alkoxy group, o A) a C _1-10 haloalkyl group, p) a C _3-10 cycloalkyl group, q) a C _6-14 aryl group, r) a 3-14 membered cycloheteroalkyl group or s) a 5-13 membered heteroaryl group. Wherein each of k) to s) is optionally substituted with 1 to 4 —ZR ¹⁰ groups;
R ¹⁰ is, in each occurrence, a) halogen, b) —CN, c) —NO ₂ , d) oxo, e) —O—Z—R ¹¹ , f) —NR ¹¹ —ZR ¹² , g _{^{) -N (O) R 11 -Z}} -R 12, h) -S (O) m R 11, i) -S (O) m O-Z-R 11, j) -S (O) m NR 11 ^{-Z-R 12, k) -C} (O) R 11, l) -C (O) O-Z-R 11, m) -C (O) NR 11 -Z-R 12, n) -C ( S) NR < ¹¹ > -ZR < ¹² >, o) -Si ( _C1-10 alkyl) ₃ , p) _C1-10 alkyl group, q) _C2-10 alkenyl group, r) _C2-10 alkynyl group, _{s) C 1-10} haloalkyl _{group, t) C 3-10} cycloalkyl _{group, u) C 6-14} aryl group, v) 3 to 14 membered cycloheteroalkyl group, or ) A 5 to 13 membered heteroaryl group, wherein each of o) to w) is replaced with 1-4 ^{R 13} groups optionally;
R ¹¹ and R ¹² are independently in each occurrence a) H, b) —OH, c) —SH, d) —S (O) ₂ OH, e) —C (O) OH, f _{) -C (O) NH 2,} g) -C (S) NH 2, h) -OC 1-10 _{alkyl, i) -S (O) m} -C 1-10 alkyl, j) -S (O) _m- OC _1-10 alkyl, k) -C (O) -C _1-10 alkyl, l) -C (O) -OC _1-10 alkyl, m) -C (S) N (C _1-10 alkyl) ) ₂ , n) -C (S) NH-C _1-10 alkyl, o) -C (O) NH-C _1-10 alkyl, p) -C (O) N (C _1-10 alkyl) ₂ , _{q) C 1-10} alkyl _{group, r) C 2-10} alkenyl _{group, s) C 2-10} alkynyl _{group, t) C 1-10} alkoxy _{group, u) C 1-10} Haroaru Le _{group, v) C 3-10} cycloalkyl _{group, w) C 6-14} aryl group, x) 3 to 14 membered cycloheteroalkyl group, or y) 5 to 13 membered heteroaryl group, wherein, each of h) -y) is optionally substituted with 1-4 -R ¹³ groups;
R ¹³ is in each occurrence a) halogen, b) —CN, c) —NO ₂ , d) oxo, e) —OH, f) —NH ₂ , g) —NH (C _1-10 alkyl) , h) _{-N (C 1-10 alkyl) 2, i) -S (O} ) m H, j) -S (O) m -C 1-10 _{alkyl, k) -S (O) 2} OH, l ) -S (O) _m -OC _1-10 alkyl, m) -S (O) _m NH ₂ , n) -S (O) _m NH (C _1-10 alkyl), o) -S (O) _m N (C _1-10 alkyl) ₂ , p) —CHO, q) —C (O) —C _1-10 alkyl, r) —C (O) OH, s) —C (O) —OC _{1-10 alkyl, t) -C (O) NH} 2, u) -C (O) NH-C 1-10 _{alkyl, v) -C (O) N} (C 1-10 _alkyl) 2, _w) -C (S ) NH _{2 , X) -C (S) NH} -C 1-10 _{alkyl, y) -C (S) N} (C 1-10 _{alkyl) 2, z) -Si (C} 1-10 _alkyl) 3, _{aa) C 1 -10} alkyl group, ab) C _2-10 alkenyl group, ac) C _2-10 alkynyl group, ad) C _1-10 alkoxy group, ae) C _1-10 alkylthio group, af) C _1-10 haloalkyl group, a) a C _3-10 cycloalkyl group, ah) a C _6-14 aryl group, ai) a 3-14 membered cycloheteroalkyl group or aj) a 5-13 membered heteroaryl group;
X is O, S, S (O), S (O) ₂ or NR ⁶ ;
Y is S (O), S (O) ₂ or C (O);
Z is in each _occurrence a) a divalent C _1-10 alkyl group, b) a divalent C _2-10 alkenyl group, c) a divalent C _2-10 alkynyl group, d) a divalent C _{A 1-10} haloalkyl group or e) a covalent bond; and m is 0, 1 or 2 in each occurrence)
And pharmaceutically acceptable salts, hydrates and esters thereof.

  In some embodiments, the compound of formula I is:

Where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X and Y are as defined herein.

In some embodiments, R ⁴ and R ⁵ can be independently selected from H and halogen. For example, R ⁴ can be H and R ⁵ can be H, Cl, or Br. In some embodiments, X can be O. In other embodiments, X can be S. In some embodiments, Y can be S (O) ₂ .

In some embodiments, R ¹ can be W—V—NH—, where:
W _{^{is, a) -C (O) R}} 14, b) -S (O) m R 14, c) -S (O) m OR 14, d) -S (O) m NR 14 R 15, e) ^{-C (O) OR 14, f} ) -C (O) NR 14 R 15, g) -C (S) R 14, h) -C (S) OR 14, i) -NR 14 R 15, j) be ^{-C (NR 14) NR 14 R} 15, k) -P (O) (oR 14) 2 or _{^{l) -B (oR 14) 2}} ;
V is a) -CR ¹⁴ R ^16- , b) -CH ₂ CR ¹⁴ R ^16- , c)-(CH = CR ¹⁴ R ¹⁶ )-or d) -BHR ^16- ;
R ¹⁴ and R ¹⁵ are independently in each occurrence a) H, b) —OH, c) —SH, d) —S (O) ₂ OH, e) —C (O) OH, f _{) -C (O) NH 2,} g) -C (S) NH 2, h) -S (O) m -C 1-10 _{alkyl, i) -S (O) m} -OC 1-10 alkyl, j ) -C (O) -C _1-10 alkyl, k) -C (O) -OC _1-10 alkyl, l) -C (O) NH-C _1-10 alkyl, m) -C (O) N (C _1-10 alkyl) ₂ , n) —C (S) NH—C _1-10 alkyl, o) —C (S) N (C _1-10 alkyl) ₂ , p) C _1-10 alkyl group, _{q) C 2-10} alkenyl _{group, r) C 2-10} alkynyl _{group, s) C 1-10} alkoxy _{groups, t) C 1-10} haloalkyl _{group, u) C 3-10} cycloalkyl Alkyl _{group, v)} a _{C 6-14} aryl group, w) 3 to 14 membered cycloheteroalkyl group, or x) 5 to 13 membered heteroaryl group, _{wherein, C 1-10} alkyl _{group, C 2- A 10} alkenyl group, a C _2-10 alkynyl group, a C _1-10 alkoxy group, a C _1-10 haloalkyl group, a C _3-10 cycloalkyl group, a C _6-14 aryl group, a 3-14 membered cycloheteroalkyl group and each of 5-13 membered heteroaryl groups are substituted with 1-4 ^{R 17} groups optionally;
R ¹⁶ is in each occurrence H or a side chain of a natural or non-natural amino acid;
R ¹⁷ is in each occurrence a) halogen, b) —CN, c) —NO ₂ , d) oxo, e) —OH, f) —NH ₂ , g) —NH (C _1-10 alkyl) , h) _{-N (C 1-10 alkyl) 2, i) -S (O} ) m H, j) -S (O) m -C 1-10 _{alkyl, k) -S (O) 2} OH, l ) -S (O) _m -OC _1-10 alkyl, m) -S (O) _m NH ₂ , n) -S (O) _m NH (C _1-10 alkyl), o) -S (O) _m N (C _1-10 alkyl) ₂ , p) —CHO, q) —C (O) —C _1-10 alkyl, r) —C (O) OH, s) —C (O) —OC _{1-10 alkyl, t) -C (O) NH} 2, u) -C (O) NH-C 1-10 _{alkyl, v) -C (O) N} (C 1-10 _alkyl) 2, _w) -C (S ) NH _{2 , X) -C (S) NH} -C 1-10 _{alkyl, y) -C (S) N} (C 1-10 _{alkyl) 2, z) -Si (C} 1-10 _alkyl) 3, _{aa) C 1 -10} alkyl group, ab) C _2-10 alkenyl group, ac) C _2-10 alkynyl group, ad) C _1-10 alkoxy group, ae) C _1-10 alkylthio group, af) C _1-10 haloalkyl group, _{ag) C 3-10} cycloalkyl group, _{ah) C 6-14} aryl group, ai) 3 to 14 membered cycloheteroalkyl group, or aj) be 5 to 13 membered heteroaryl group; and m is hereby As defined in the document.

In some embodiments, W can be —C (O) OR ¹⁴ and V can be —CR ¹⁴ R ¹⁶ —, where R ¹⁴ and R ¹⁶ are as defined herein. That's right. In some embodiments, R ¹ can be an N-linked, free carboxyl or carboxyl protected, natural or non-natural D-alpha-amino acid. In other embodiments, R ¹ can be an N-linked, free carboxyl or carboxyl protected, natural or non-natural L-alpha-amino acid. In other embodiments, the amino acid derivative can be a natural amino acid derivative.

In some embodiments, R ¹⁶ can be isopropyl. In certain embodiments, R ¹ can be valine. In certain embodiments, R ¹ can be D-valine.

In some embodiments, R ² and R ³ are independently H, oxo, —S (O) _m OR ⁸ , —S (O) _m NR ⁸ R ⁹ , —C (O) R ⁸ , ^{-C (S) OR 8, -C} (S) R 8, -C (S) NR 8 R 9, -C (NR 8) NR 8 R 9, C 1-10 _{alkyl, C 2-10} alkenyl , C _2-10 alkynyl group, C _1-10 haloalkyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, 3-14 membered cycloheteroalkyl group or 5-13 membered heteroaryl group Obtained, wherein C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group, C _1-10 haloalkyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, 3- 14-membered cycloheteroalkyl group and 5-13 membered Each of the heteroaryl groups can be optionally substituted with 1 to 4 -ZR ¹⁰ groups. In certain embodiments, R ² and R ³ are independently H, oxo, —C (O) R ⁸ , a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group. And a C _3-10 cycloalkyl group, wherein each of the C _1-10 alkyl group, the C _2-10 alkenyl group, the C _2-10 alkynyl group and the C _3-10 cycloalkyl group is optionally Accordingly, it may be substituted with 1 to 4 -ZR ¹⁰ groups. For example, R ² and R ³ are independently H, oxo, —C (O) CH ₃ , —C (O) CH ₂ CH ₃ , —C (O) CH (CH ₃ ) ₂ , methyl group and It can be selected from an ethyl group.

In some embodiments, R ² and R ³ can be taken together with a nitrogen atom common to them to form —N═CR ⁷ R ⁷ , —N═O, or —N═N—R ^8. . In certain embodiments, R ² and R ³ , together with their common nitrogen atom, can form —N═CR ⁷ R ⁷ , wherein each R ⁷ is independently H, halogen, —OR ⁸ , —NR ⁸ R ⁹ , C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group, C _1-10 haloalkyl group, C _3-10 cycloalkyl group, C _6-14 aryl group which may be cycloheteroalkyl group, or a 5-13 membered heteroaryl group 3-14 _{membered, C 1-10 alkyl, C 2-10 alkenyl, C 2-10} alkynyl group, Each of the C _1-10 haloalkyl group, the C _3-10 cycloalkyl group, the C _6-14 aryl group, the 3-14 membered cycloheteroalkyl group and the 5-13 membered heteroaryl group is optionally selected from 1 to 4- It may be substituted with -R ¹⁰ group. For example, R ² and R ³ , together with their common nitrogen atom, can form —N═CHR ⁷ , where R ⁷ is —NH ₂ , —NH (C _1-10 alkyl ) Or —N (C _1-10 alkyl) ₂ . In certain embodiments, —NR ² R ³ is —NH ₂ , —NO ₂ , —NHC (O) CH ₃ , —N (CH ₂ CH ₂ OH) C (O) CH ₃ , —NHCH ₃ , — _{NHCH 2 CH 3, -N (CH} 3) CH 2 CH 3, -N (CH 2 CH 3) 2, -NHCH 2 CH 2 OH, in -NHCH ₂ CH ₂ Cl or -N = CHN _{(CH 3) 2} possible.

In some embodiments, R ² can be —C (O) OR ⁸ , where R ⁸ is H, —C (O) R ¹¹ , —C (O) OR ¹¹ , —C ( O) NR ¹¹ R ¹² , C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group, C _1-10 haloalkyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, It may be selected from a 3-14 membered cycloheteroalkyl group and a 5-13 membered heteroaryl group, wherein C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group, C _1- Each of the ₁₀ haloalkyl group, the C _3-10 cycloalkyl group, the C _6-14 aryl group, the 3-14 membered cycloheteroalkyl group and the 5-13 membered heteroaryl group is optionally substituted with 1-4 substituted with ^{-Z-R 10} group It can be. For example, R ⁸ can be selected from H, C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group and C _6-14 aryl group, wherein C _1-10 alkyl group, Each of the C _2-10 alkenyl group, C _2-10 alkynyl group and C _6-14 aryl group may be optionally substituted with 1 to 4 —ZR ¹⁰ groups. In certain embodiments, R ⁸ can be selected from methyl, ethyl, propyl, isopropyl, isobutyl, butyl, hexyl and butynyl groups, each of which is halogen, —S (O _{^{) m R 11, -S (O}} ) m O-Z-R 11, -S (O) m NR 11 -Z-R 12, -C (O) R 11, -C (O) O-Z-R ¹¹ , —C (O) NR ¹¹ —ZR ¹² , optionally substituted with 1 to 4 groups independently selected from a C _6-14 aryl group and a 5-13 membered heteroaryl group. obtain. In certain embodiments, R ⁸ is methyl, ethyl, propyl, isopropyl, isobutyl, butyl, hexyl, 3-butynyl, 4-butynyl, 2-fluoroethyl, 2-chloroethyl. It can be selected from the group, 2-bromoethyl group, 2-methanesulfonylethyl group, 3-chloropropyl group and benzyl group.

In certain embodiments, when R ² is —C (O) OR ⁸ , R ⁸ is optionally 1-4 groups independently selected from halogen and C _1-10 alkyl groups. Or a substituted phenyl group. In certain embodiments, R ⁸ can be selected from a phenyl group, a tolyl group, a fluorophenyl group, and a chlorophenyl group.

In some embodiments, R ² can be —C (O) NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are independently H, C _1-10 alkyl group, C ₂₋ May be selected from ₁₀ alkenyl groups, C _2-10 alkynyl groups, C _3-10 cycloalkyl groups, C _6-14 aryl groups, 3-14 membered cycloheteroalkyl groups and 5-13 membered heteroaryl groups; _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, 3-14 membered cycloheteroalkyl group and 5-13 membered Each of the heteroaryl groups can be optionally substituted with 1 to 4 -ZR ¹⁰ groups. In certain embodiments, R ⁹ can be H or a C _1-10 alkyl group. For example, R ⁸ can be H or a methyl group.

In some embodiments, when R ² is —C (O) NR ⁸ R ⁹ , R ⁸ is H, a C _1-10 alkyl group, a C _3-10 cycloalkyl group, a C _6-14 aryl group. , A 3-14 membered cycloheteroalkyl group and a 5-13 membered heteroaryl group, a C _1-10 alkyl group, a C _3-10 cycloalkyl group, a C _6-14 aryl group, a 3-14 member Each of the cycloheteroalkyl groups and 5- to 13-membered heteroaryl groups can be optionally substituted with 1 to 4 —Z—R ¹⁰ groups. For example, a —Z—R ¹⁰ group, in each occurrence, is halogen, —O—Z—R ¹¹ , —NR ¹¹ —Z—R ¹² , a C _1-10 alkyl group, a C _1-10 alkoxy group, C _{1 It} may be a _-10 haloalkyl group, a 3-14 membered cycloheteroalkyl group, a 5-13 membered heteroaryl group or a phenyl group, wherein a C _1-10 alkyl group, a C _1-10 alkoxy group, a C _{1- 10} haloalkyl group, 3-14 membered cycloheteroalkyl group, each of the heteroaryl group or a phenyl group 5 to 13 membered, may be substituted with 1-4 ^{R 13,} if necessary. In certain embodiments, R ⁸ can be H or optionally substituted with 1-4 groups independently selected from halogen, a phenyl group, and a 5-6 membered heteroaryl group. A C _1-6 alkyl group, wherein each of the phenyl group and the 5-6 membered heteroaryl group can be optionally substituted with 1-4 R ¹³ . In certain embodiments, R ⁸ can be selected from H, methyl group, ethyl group, isopropyl group, cyclopentyl group, benzyl group, fluorobenzyl group, phenethyl group, thienylmethyl group, and thienylethyl group. In certain embodiments, R ⁸ can be a phenyl group or a 5-13 membered heteroaryl group, each of which can be optionally substituted with 1 to 4 —Z—R ¹⁰ groups. . In certain embodiments, R ⁸ can be selected from a phenyl group, a 2,3-dihydrobenzo [b] [1,4] dioxinyl group, a thienyl group, a pyridyl group, and an isoxazolyl group, wherein the phenyl group, thienyl group, pyridyl group Each of the groups and isoxazolyl groups is independently selected from halogen, —O—Z—R ¹¹ , —NR ¹¹ —ZR ¹² , a C _1-10 alkyl group and a C _1-10 haloalkyl group. Can be optionally substituted with groups.

In some embodiments, R ² can be —S (O) _m R ⁸ . In some embodiments, R ² can be —S (O) _m OR ⁸ . In certain embodiments, R ² can be —S (O) R ⁸ or —SO ₂ R ⁸ . In some embodiments, when R ² is —S (O) R ⁸ or —SO ₂ R ⁸ , R ⁸ is H, a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _{2− A 10} alkynyl group, a C _1-10 haloalkyl group, a C _3-10 cycloalkyl group, a C _6-14 aryl group, a 3-14 membered cycloheteroalkyl group and a 5-13 membered heteroaryl group, wherein A C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C _1-10 haloalkyl group, a C _3-10 cycloalkyl group, a C _6-14 aryl group, a 3-14 membered Each of the cycloheteroalkyl group and the 5- to 13-membered heteroaryl group can be optionally substituted with 1 to 4 -ZR ¹⁰ groups. For example, R ⁸ can be selected from H, a C _1-10 alkyl group, a C _6-14 aryl group, and a 5-13 membered heteroaryl group, a C _1-10 alkyl group, a C _6-14 aryl group, and 5 Each ˜13 membered heteroaryl group may be optionally substituted with 1 to 4 —Z—R ¹⁰ groups. In certain embodiments, the —Z—R ¹⁰ group, in each occurrence, can independently be a halogen, a C _1-10 alkyl group, a C _1-10 haloalkyl group, or a phenyl group. In certain embodiments, R ⁸ can be selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a butyl group, and a hexyl group, each of which is from a halogen and a C _1-10 haloalkyl group. It may be optionally substituted with 1 to 4 groups independently selected. In certain embodiments, R ⁸ can be selected from a methyl group, an ethyl group, an isopropyl group, a 2-chloromethyl group, and a 2-trifluoromethyl group. In certain embodiments, R ⁸ can be selected from a phenyl group and a 5- or 6-membered heteroaryl group, each of which is independently selected from a halogen and a C _1-10 alkyl group Three groups may be optionally substituted. For example, a 5 or 6 membered heteroaryl group can be a thienyl group or an isoxazolyl group. In certain embodiments, R ⁸ can be selected from a phenyl group, a fluorophenyl group, a dimethylisoxazolyl group, and a dichlorothienyl group.

In some embodiments, R ³ is H, —S (O) _m R ⁸ , —S (O) _m OR ⁸ , —S (O) _m NR ⁸ R ⁹ , —C (O) R ⁸ , ^{-C (S) OR 8, -C} (S) R 8, -C (S) NR 8 R 9, -C (NR 8) NR 8 R 9, C 1-10 _{alkyl, C 2-10} alkenyl , C _2-10 alkynyl group, C _1-10 haloalkyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, 3-14 membered cycloheteroalkyl group or 5-13 membered heteroaryl group Obtained, wherein C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group, C _1-10 haloalkyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, 3- 14-membered cycloheteroalkyl group and 5-13 membered heteroa Each of the reel groups can be optionally substituted with 1 to 4 -ZR ¹⁰ groups. For example, R ³ is H, —S (O) _m R ⁸ or a C _1-10 alkyl group optionally substituted with 1 to 4 —ZR ¹⁰ groups (eg, methyl group, ethyl group). Propyl group, butyl group, pentyl group, hexyl group and heptyl group). In certain embodiments, when R ³ is —S (O) _m R ⁸ , R ⁸ can be a phenyl group. In certain embodiments, R ³ can be selected from H, a methyl group, an ethyl group, and a fluorophenylsulfonyl group.

In some embodiments, R ² and R ³ can be taken together with their common nitrogen atom to form a 3-14 membered cycloheteroalkyl group or a 5-13 membered heteroaryl group, wherein And each of the 3 to 14 membered cycloheteroalkyl group and the 5 to 13 membered heteroaryl group can be optionally substituted with 1 to 4 —Z—R ¹⁰ groups. In certain embodiments, the 3-14 membered cycloheteroalkyl group includes 3-14 membered cyclic urea group, 3-14 membered cyclic carbamate group, 3-14 membered cyclic sulfinamide group, and 3-14. Member cyclic sulfonamide groups may be excluded. In certain embodiments, R ² and R ³ can be taken together with their common nitrogen atom to form a 3-14 membered cycloheteroalkyl group, which is independent of O, S and N. Optionally selected from 1, 2 or 3 additional ring heteroatoms and optionally substituted with 1 to 4 —Z—R ¹⁰ groups. In certain embodiments, R ² and R ³ can be taken together with their common nitrogen atom to form a 5- or 6-membered cycloheteroalkyl group, each of which is optionally It can be substituted with 1 to 4 -ZR ¹⁰ groups. For example, the 5- or 6-membered cycloheteroalkyl group is selected from a pyrrolidinyl group, an oxazolinyl group, a thiazolinyl group, an isothiazolinyl group, an imidazolinyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, a thiomorpholinyl group, and a 1,3-oxadinanyl group. Thus, the —Z—R ¹⁰ group may be selected from halogen, oxo and C _1-6 alkyl groups in each occurrence.

In certain embodiments, R ² and R ³ can be taken together with their common nitrogen atom to form a 5-13 membered heteroaryl group, which is optionally 1, 2, 3 Or it may contain 4 additional N atoms and may optionally be substituted with 1 to 4 —Z—R ¹⁰ groups. In certain embodiments, the 5-13 membered heteroaryl group may be selected from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, purinyl and carbazolyl groups. In certain embodiments, R ² and R ³ together with their common nitrogen atom are 5- or 6-membered hetero, optionally substituted with 1 to 4 —Z—R ^10. An aryl group can be formed. For example, the 5- or 6-membered heteroaryl group can be selected from pyrrolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups. In certain embodiments, Z can be selected from a divalent C _1-4 alkyl group and a covalent bond. In certain embodiments, R ¹⁰ is —CN, —O—Z—R ¹¹ , —NR ¹¹ —Z—R ¹² , —C (O) O—Z—R ¹¹ , —C (O) NR ^11. -ZR ¹² , -Si (C _1-10 alkyl) ₃ , C _1-10 alkyl group, C _1-10 haloalkyl group, C _3-10 cycloalkyl group, C _6-14 aryl group and 5 to 13 members In which a C _1-10 alkyl group, a C _6-14 heteroaryl group, a C _3-10 cycloalkyl group, a C _6-14 aryl group and a 5-13 membered heteroaryl group Each of can be optionally substituted with 1 to 4 R ¹³ groups.

In some embodiments, when R ² can be —C (O) OR ⁸ or —C (O) NR ⁸ R ⁹ , R ³ and the R ⁸ portion of R ² are attached to them.

Together to form a 3-14 membered cyclic urea group or a 3-14 membered cyclic carbamate group, each of which is optionally substituted with 1 to 4 -ZR ¹⁰ groups. Can be done. In certain embodiments, the 3-14 membered cyclic urea group or the 3-14 membered cyclic carbamate group can be a 5-12 membered cyclic urea group or a 5-12 membered cyclic carbamate group. In certain embodiments, R ⁹ can be H or a methyl group. For example, a 5- to 12-membered cyclic urea group or a 5- to 12-membered cyclic carbamate group is a 5-membered cyclic urea group, a 6-membered cyclic urea group, a 5-membered cyclic carbamate group, or a 6-membered cyclic carbamate group. obtain.

In some embodiments, when R ² can be —SOR ⁸ or —SO ₂ R ⁸ , R ³ and the R ⁸ portion of R ² are taken together with N and S to which they are attached, respectively. Can form a 3-14 membered cyclic sulfinamide group or a 3-14 membered cyclic sulfonamide group, each of which can optionally be substituted with 1 to 4 -ZR ¹⁰ groups. . In certain embodiments, the 3-14 membered cyclic sulfinamide group or the 3-14 membered cyclic sulfonamide group can be a 5-12 membered cyclic sulfinamide group or a 5-12 membered cyclic sulfonamide group. . For example, a 5- to 12-membered cyclic sulfinamide group or a 5- to 12-membered cyclic sulfonamide group includes an S-oxoisothiazolidin-2-yl group, an S-oxothiazinan-2-yl group, an S, S-dioxoiso It may be a thiazolidin-2-yl group or an S, S-dioxothiazinan-2-yl group.

In the present teachings, it is to be understood that certain compounds within the genus identified by Formula I can be excluded. For example, when X is O, -Y-R ¹ is located at the ^2- position, -NR ² R ³ is located at the 7-position, and R ² is hydrogen, R ³ is hydrogen, C _1-5 Compounds that are alkyl groups or —C (O) C _1-5 alkyl groups may be excluded from the present teachings. A compound wherein each of R ² and R ³ is a C _1-5 alkyl group when X is O, —Y—R ¹ is located in position ² and —NR ² R ³ is located in position 7; It can be excluded from the present teachings. Also, -Y-R ¹ is located at the 3-position, X is O, -NR ² R ³ is located at the 7-position, R ² is H, and R ³ is H, C _1-5 alkyl compound is a group or a -C _{(O) C 1-5} alkyl group; and ^{-Y-R 1} is located at the 3-position, X is O, ^-NR 2 ^{R 3} is located at the 7, ^{R 2} and Compounds wherein each R ³ is a C _1-5 alkyl group can be excluded from the present teachings. In addition, the above specific compounds where -Y-R ¹ is located at the 2 or 3 position and -NR ² R ³ is located at the 8 position can be excluded from the present teachings.

  Compounds of the present teachings include those shown in Table 1 below:

.

  Prodrugs of the compounds disclosed herein are provided according to the present teachings. As used herein, a “prodrug” is a compound having a moiety (“parent”) that produces, produces or releases a compound of the present teachings when administered to a mammalian subject. Compound "). Prodrugs can be prepared by modifying functional groups present in the compound, which modifications are made in such a way that the modification is cleaved from the parent compound by routine manipulation or in vivo. Examples of prodrugs include one or more molecular moieties attached to a hydroxyl group, amino group, sulfhydryl group, or carboxyl group of a compound, and in vivo when administered to a mammalian subject. Examples include compounds as described herein that are cleaved to form a free hydroxyl group, a free amino group, a free sulfhydryl group, or a free carboxyl group, respectively. Examples of prodrugs may include acetate, formate and benzoate derivatives of alcohol and amine functions in the compounds of the present teachings. The preparation and use of prodrugs is described in T.W. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.E. C. S. Symposium Series and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, the entire disclosure of which is incorporated herein by reference for all purposes.

Ester forms of the compounds described in the present teachings include pharmaceutically acceptable esters known in the art that can be metabolized to the free acid form, such as the free carboxylic acid form, in the mammalian body. Examples of suitable esters include alkyl esters (eg 1 to 10 carbon atoms alkyl), cycloalkyl esters (eg 3 to 10 carbon atoms), aryl esters (eg 6 to 14 carbon atoms). Atoms (including 6 to 10 carbon atoms) and their heterocyclic analogues (eg 3 to 14 ring atoms, of which 1-3 are oxygen, nitrogen and sulfur) The alcohol residue may further have a substituent. In some embodiments, the ester of a compound disclosed herein is a C _1-10 alkyl ester (eg, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester). Pentyl ester, isopentyl ester, neopentyl ester, hexyl ester, cyclopropylmethyl ester and benzyl ester), C _3-10 cycloalkyl ester (eg cyclopropyl ester, cyclobutyl ester, cyclopentyl ester and cyclohexyl ester) or aryl Esters can be esters, such as phenyl esters and tolyl esters.

Pharmaceutically acceptable salts of compounds of formula I that may have an acidic moiety can be formed using organic or inorganic bases. Depending on the number of acidic hydrogens available for deprotonation, both monoanionic and polyanionic salts are contemplated. Suitable salts formed with bases include metal salts (eg, alkali metal salts or alkaline earth metal salts, eg, sodium, potassium or magnesium salts); ammonia salts and organic amine salts (eg, morpholine). , Thiomorpholine, piperidine, pyrrolidine, mono-, di- or tri-lower alkylamine (eg ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine) or mono-, di- -Or trihydroxy lower alkylamines (such as those formed with mono-, di- or triethanolamine). Specific non-limiting examples of inorganic bases include NaHCO ₃ , Na ₂ CO ₃ , KHCO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , LiOH, NaOH, KOH, NaH ₂ PO ₄ , Na ₂ HPO ₄ and Na ₃ PO ₄ is mentioned. An internal salt can also be formed. Similarly, when a compound disclosed herein contains a basic moiety, salts can be formed with organic and inorganic acids. For example, the salts include the following acids: acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, dichloroacetic acid, ethenesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hippuric acid, hydrobromic acid, Hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucoic acid, naphthalenesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, phthalic acid, propionic acid, It can be formed from succinic acid, sulfuric acid, tartaric acid, toluenesulfonic acid and other known pharmaceutically acceptable acids.

  The present teachings also provide a pharmaceutical composition comprising at least one compound described herein and one or more pharmaceutically acceptable carriers, excipients or diluents. Examples of such carriers are well known to those skilled in the art and are described, for example, in Remington: The Science and Practice of Pharmacy, 20th edition, Alfonso R., et al. Acceptable, such as the procedure described in Gennaro (ed.), Lippincott Williams & Wilkins, Baltimore, MD (2000), the entire disclosure of which is incorporated herein by reference for all purposes. It can be prepared according to pharmaceutical procedures. As used herein, “pharmaceutically acceptable” refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological point of view and does not adversely interact with the active ingredient. Point to. Accordingly, pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and biologically acceptable. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

  The compounds of the present teachings can be useful for the treatment or inhibition of pathological conditions or disorders in mammals, eg, humans. Accordingly, the present teachings relate to a compound of the present teachings (or a pharmaceutically acceptable salt, hydrate or ester thereof) or one or more compounds of the present teachings in combination with or in combination with a pharmaceutically acceptable carrier. It includes a method of providing a mammal with a pharmaceutical composition containing it. The compounds of the present teachings can be administered alone or in combination with other therapeutically effective compounds or therapies for the treatment or inhibition of pathological conditions or disorders. As used herein, “therapeutically effective” refers to a substance or amount that elicits a desired biological activity or effect.

  The present teachings relate to pathological conditions or disorders, eg, conditions that are wholly or partially mediated by one or more MMPs or conditions characterized by an MMP / TIMP imbalance (eg, rheumatoid arthritis, osteoarthritis). For treating or inhibiting diseases characterized by the accumulation of inflammatory cells (eg, chronic obstructive pulmonary disease and asthma), atherosclerosis, heart failure, fibrosis, emphysema and tumor growth, invasion and metastasis) Further included is the use of a compound disclosed herein as an active therapeutic substance. Accordingly, the present teachings further provide methods for treating these pathological conditions and disorders using the compounds disclosed herein. As used herein, “treating” refers to partially or completely reducing and / or ameliorating the above condition. In some embodiments, the methods are described herein for identifying a mammal having a pathological condition or disorder characterized by an MMP / TIMP imbalance and a therapeutically effective amount for the mammal. Providing a compound. In some embodiments, the method comprises administering to the mammal a pharmaceutical composition comprising a compound disclosed herein in combination with or in combination with a pharmaceutically acceptable carrier. .

  The present teachings relate to pathological conditions or disorders, eg, conditions that are wholly or partially mediated by one or more MMPs or conditions characterized by an MMP / TIMP imbalance (eg, rheumatoid arthritis, osteoarthritis). Active therapeutic to prevent atherosclerosis, atherosclerosis, multiple sclerosis, heart failure, spinal cord injury, skin aging, fibrosis, lung cancer, skin cancer, chronic obstructive pulmonary disease, asthma, obesity and diabetes) Further included is the use of a compound disclosed herein as the substance. Accordingly, the present teachings further provide methods for preventing these pathological conditions and disorders using the compounds described herein. In some embodiments, the method comprises identifying a mammal that may potentially have a pathological condition or disorder characterized by an MMP / TIMP imbalance, and a therapeutically effective amount of the book in the mammal. Providing a compound described in the specification. In some embodiments, the method comprises administering to the mammal a pharmaceutical composition comprising a compound disclosed herein in combination with or in combination with a pharmaceutically acceptable carrier. .

  The compounds of the present teachings can be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers include one or more that can also act as flavorings, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet disintegrants or encapsulating materials. Can be mentioned. The compounds can be formulated in a conventional manner, for example, in a manner similar to that used for known anti-inflammatory agents. Oral formulations containing the active compounds disclosed herein can be any tablet, capsule, buccal form, troche, electuary and oral liquid, suspension or solution. Conventionally used oral forms may be included. In powders, the carrier can be a finely divided solid, which is a mixture with the finely divided active compound. In tablets, the active compound can be mixed with the carrier having the necessary compression properties in suitable proportions and compacted to the desired shape and size. Powders and tablets may contain up to 99% active compound.

  Capsules can contain active compounds and inert fillers and / or diluents (eg, pharmaceutically acceptable starches (eg, corn, potato or tapioca starch), sugars, artificial sweeteners, powdered cellulose (eg, , Crystalline and microcrystalline cellulose), flour, gelatin, gum, etc.).

  Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods, and include pharmaceutically acceptable diluents, binders, lubricants, disintegrants, surface modifiers (surfactants). ), Suspensions or stabilizers (magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, carboxymethylcellulose Calcium, polyvinylpyrrolidine, alginic acid, gum arabic, xanthan gum, sodium citrate, silicate complex, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, chloride Thorium may utilize containing low melting waxes and ion exchange resins). Preferred surface modifiers include nonionic and anionic surface modifiers. Representative examples of surface modifiers include poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan ester, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, aluminum magnesium silicate And triethanolamine. The oral formulations herein can vary the absorption of the active compound using standard delayed or sustained release formulations. The oral formulation may also consist of administering the active compound in water or fruit juice, containing appropriate solubilizers or emulsifiers if necessary.

  Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active compounds described herein can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, mixtures thereof or pharmaceutically acceptable oils or fats. obtain. Liquid carriers may be other suitable pharmaceutical additives (eg, solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavorings, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers. And an osmotic pressure adjusting agent). Examples of liquid carriers for oral and parenteral administration include water (including in particular additives such as cellulose derivatives such as sodium carboxymethylcellulose), alcohols (monohydric and polyhydric alcohols such as And glycols) and their derivatives and oils (eg, fractionated palm oil and peanut oil). For parenteral administration, the carrier can be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers can be used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.

  Liquid pharmaceutical compositions can be sterile solutions or suspensions, and can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The composition for oral administration may be in a liquid form or a solid form.

  The pharmaceutical composition may be in unit dosage form such as tablets, capsules, powders, solutions, suspensions, emulsions, granules or suppositories. In such form, the pharmaceutical composition can be further subdivided into unit doses containing appropriate quantities of the active compound. The unit dosage form can be a packaged composition, eg, a sachet, including a sachet, vial, ampoule, prefilled syringe, or liquid. Alternatively, the unit dosage form can be the capsule itself or the tablet itself, or it can be a suitable number of such optional compositions in package form. Such unit dosage forms can contain from about 1 mg / kg of active compound to about 500 mg / kg of active compound and can be given in a single dose or in two or more doses. Such doses may be used in any manner useful in delivering the active compound to the recipient's bloodstream (oral, via implant, parenterally (intravenous, intraperitoneal and subcutaneous injection). Including), rectal, vaginal and transdermal). Such administration includes pharmaceutically acceptable salts, hydrates and esters of the compounds of the present teachings as lotions, creams, foams, patches, suspensions, solutions and suppositories (rectal and vaginal). This is done using the compounds of the present teachings.

  When administered to treat or inhibit a particular disease state or disorder, the effective dosage may vary depending on the particular compound utilized, the mode of administration and / or the severity of the condition being treated and the individual being treated. It is understood that it can vary depending on different physical factors. In therapeutic applications, the compounds of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. In prophylactic applications, the compounds of the present teachings can be provided to patients who may be suffering from a disease in an amount sufficient to prevent or at least delay the symptoms of the disease and its complications. The dosage used to treat a particular individual typically needs to be determined subjectively by the attending physician. Related variables include the specific condition and its context and the patient's size, age and response pattern.

  In some cases, for example, when targeting the lung, devices (eg, metered dose inhalers, respiratory activated inhalers, multi-dose dry powder inhalers, pumps, squeezed-actuated nebulized dispensers) It may be desirable to administer the compound directly into the patient's respiratory tract using a spray dispenser), aerosol dispenser and aerosol nebulizer. For intranasal or bronchial administration by inhalation, the compounds of the present teachings can be formulated into a liquid composition, a solid composition or an aerosol composition. Liquid compositions include, for illustrative purposes, one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents. Liquid compositions can be administered, for example, by a pump or a squeezed spray spray dispenser. The solvent can be, for example, isotonic saline or bacteriostatic water. A solid composition can be a powder preparation comprising, for illustrative purposes, one or more compounds of the present teachings mixed with lactose or other inert powders acceptable for intrabronchial use, eg, an aerosol It can be administered by a dispenser or a device that breaks or punctures the capsule enclosing the solid composition and delivers the solid composition for inhalation. Aerosol compositions can include one or more compounds of the present teachings, propellants, surfactants and cosolvents for illustrative purposes, and can be administered, for example, by a quantitative device. The propellant can be a chlorofluorocarbon (CFC), hydrofluoroalkane (HFA) or other physiologically and environmentally acceptable propellant.

  The compounds described herein can be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds or pharmaceutically acceptable salts thereof can be prepared in water suitably mixed with a surfactant such as hydroxyl-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oil. Under ordinary conditions of storage and use, these preparations typically contain a preservative that inhibits microbial growth.

  Pharmaceutical forms suitable for injection may include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In a preferred embodiment, the form is sterilized and its viscosity is that which can flow through the syringe. The form is preferably stable under the conditions of manufacture and storage and can be protected from contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

  The compounds described herein can be administered transdermally, i.e., through the body surface and the lumen of bodily tracts including epithelial and mucosal tissues. Such administration uses lotions, creams, foams, patches, suspensions, solutions and suppositories (rectal and vaginal) compounds of the present teachings (including pharmaceutically acceptable salts thereof). Can be done. Topical formulations that deliver active compounds through the epidermis may be useful for the topical treatment of inflammation and arthritis.

  Transdermal administration can be accomplished by using a transdermal patch comprising an active compound and a carrier that can be inert to the active compound, can be non-toxic to the skin, The active compound can then be delivered through the skin and into the bloodstream for systemic absorption. The carrier may take any number of forms such as creams and ointments, pastes, gels, and closed devices. Creams and ointments can be oil-in-water or water-in-oil viscous liquids or semisolid emulsions. Pastes containing absorbent powder dispersed in petroleum or hydrophilic petroleum containing the active compound may also be suitable. By using various closed system devices (eg, a semipermeable membrane covering a reservoir containing an active compound with or without a carrier, or a matrix containing an active compound), Can be released into the bloodstream. Other closed system devices are known in the literature.

  The compounds described herein can be administered rectally or vaginally in the form of a conventional suppository. Suppository formulations may be made from conventional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and with or without the addition of glycerin. Water-soluble suppository bases such as polyethylene glycols of various molecular weights can also be used.

  The compounds of the present teachings can be introduced into host cells in vitro or in vivo by using lipid formulations or nanocapsules. Lipid formulations and nanocapsules can be prepared by methods known in the art.

  In order to increase the effectiveness of the compounds of the present teachings, it may be desirable to combine the compounds with other agents that are effective in treating the target disease. For inflammatory diseases, other active compounds (ie other active ingredients or agents) that are effective in their treatment, particularly in the treatment of asthma and arthritis, may be administered with the active compounds of the present teachings. The other agent can be administered at the same time as the compound disclosed herein or can be administered at a different time.

  Throughout this description, when the composition is described as having, including, or containing certain components, or when the process is described as having, including, or including certain process steps, Compositions of the present teachings consist essentially of the listed components, or consist of the listed components, and the processes of the present teachings consist essentially of, or are listed in, the listed process steps. It is contemplated to consist of process steps.

  In this application, when an element or component is said to be included in and / or selected from the list of listed elements or components, the element or component is listed It should be understood that it can be any one of the elements or components and can be selected from the group consisting of two or more of the listed elements or components.

  The terms “include / include”, “include / includes”, “include / include”, “have”, “has” or “having” The use of "" is generally understood to be unlimited and non-limiting unless specifically stated otherwise.

  The use of the singular herein includes the plural (and vice versa) unless specifically stated otherwise. Further, when the term “about” is used before a quantitative value, the present teachings also encompass the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ± 5% variation from the nominal value.

  It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present teachings are operable. Moreover, two or more steps or actions can be performed simultaneously.

  As used herein, “compound” means unless otherwise understood from the context of the description or one particular form of the compound (ie, the compound itself or a pharmaceutically acceptable salt thereof, water Unless explicitly limited to a hydrate or ester), it refers to the compound itself as well as pharmaceutically acceptable salts, hydrates and esters thereof.

  As used herein, “natural amino acid” refers to an amino acid normally present in a natural protein, such as an L-α-amino acid. Examples of natural amino acids include glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, lysine, hydroxylysine, histidine, phenylalanine, tyrosine, tryptophan, Proline and 4-hydroxyproline are mentioned.

  As used herein, “non-natural amino acid” refers to an amino acid that is not normally present in a protein. For example, an unnatural amino acid is an epimer of a natural L-amino acid, ie, an amino acid having a D-configuration; a β-amino acid; an α, α-disubstituted amino acid; An α-amino acid that has been shortened to a group or extended to a maximum of 10 carbon atoms (eg, an α-aminoalkanoic acid having a straight chain of 5 carbon atoms and up to 10 carbon atoms); substitution Unsubstituted or substituted aromatic amino acids (eg, phenylglycine) or substituted phenylalanines; cyclic amino acids other than natural cyclic amino acids; and the backbone methylene group is a boron group, eg, —BHR ′ — (R ′ Can refer to boron analogs that are substituted by side chains of natural or non-natural amino acids. Examples of non-natural amino acids include β-alanine, taurine, α-aminobutyric acid, γ-aminoisobutyric acid, β-aminoisobutyric acid, homocysteine, homoserine, cysteine sulfinic acid, cysteic acid, ferrinin, isobarthine, 2,3- Diaminosuccinic acid, γ-hydroxyglutamic acid, α-aminoadipic acid, α, ε-diaminopimelic acid, α, β-diaminopropionic acid, α, γ-diaminobutyric acid, ornithine, citrulline, homocitrulline, saccharopine, azetidine-2- Carboxylic acid, 3-hydroxyproline, pipecolic acid, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine, monoiodotyrosine, 3,5-diiodotyrosine, 3,5,3'-triiodothyronine, thyroxine and azaserine Is mentioned.

  As used herein, an “amino acid derivative” refers to a natural or non-natural amino acid having a carboxylic acid group substituted by another chemical substituent or chemical. Such other chemical substituents or chemicals include acyl groups, thiol groups, sulfonic acid groups, sulfuric acid groups, sulfonate groups, sulfonamido groups, ester groups, amide groups, amine groups, amidine groups, phosphonic acid groups, Mention may be made of phosphonate groups, boronic acid groups and boronic ester groups.

  As used herein, an “N-linked natural amino acid” is a natural amino acid whose basic amino group lacks an amine hydrogen, and whose hydrogen is replaced by a covalent bond with another chemical substance. Refers to the amino acid. As used herein, an “N-linked non-natural amino acid” is one in which the basic amino group lacks an amine hydrogen and the hydrogen is replaced with another chemical entity by a covalent bond. Refers to an unnatural amino acid. As used herein, an “N-linked amino acid derivative” is an amino acid derivative in which the basic amino group lacks an amine hydrogen and the hydrogen is replaced with another chemical substance by a covalent bond Refers to that.

  As used herein, “free carboxyl” refers to a carboxylic acid group, for example, a free carboxyl natural amino acid refers to a natural amino acid having a carboxylic acid group at the terminal position. As used herein, “carboxyl protected” refers to a carboxylic acid group that is protected or blocked to prevent unwanted side reactions from occurring due to the carboxylic acid group. Carboxyl protected molecules can be converted to free carboxyl molecules under appropriate conditions.

  As used herein, a “tricyclic core” of a compound of formula I is:

Wherein X is as defined herein.

  As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

  As used herein, “oxo” refers to a double bond oxygen (ie, ═O).

As used herein, “alkyl” refers to a straight or branched chain saturated hydrocarbon group. In some embodiments, the alkyl group can have 1 to 10 carbon atoms (eg, 1 to 6 carbon atoms). Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (eg, n-propyl and isopropyl), butyl (eg, n-butyl, isobutyl, s-butyl, t-butyl), pentyl group ( For example, n-pentyl, isopentyl, neopentyl) and the like. In some embodiments, the alkyl group can be substituted with up to four independently selected —Z—R ¹⁰ or R ¹³ groups, wherein Z, R ¹⁰ and R ¹³ are as defined herein. As described in the book. Lower alkyl groups typically have up to 4 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl (eg, n-propyl and isopropyl) and butyl groups (eg, n-butyl, isobutyl, s-butyl, t-butyl).

As used herein, “alkenyl” refers to a straight or branched alkyl group having one or more carbon-carbon double bonds. In some embodiments, an alkenyl group can have 2 to 10 carbon atoms (eg, 2 to 6 carbon atoms). Examples of alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl groups and the like. The one or more carbon-carbon double bonds may be present internally (eg 2-butene) or terminal (eg 1-butene). In some embodiments, an alkenyl group can be substituted with up to four independently selected —Z—R ¹⁰ or R ¹³ groups, wherein Z, R ¹⁰ and R ¹³ are as defined herein. As described in the book.

As used herein, “alkynyl” refers to a straight or branched alkyl group having one or more carbon-carbon triple bonds. In some embodiments, an alkynyl group can have 2 to 10 carbon atoms (eg, 2 to 6 carbon atoms). Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and the like. The one or more carbon-carbon triple bonds may be internal (eg, 2-butyne) or terminal (eg, 1-butyne). In some embodiments, an alkynyl group can be substituted with up to four independently selected —Z—R ¹⁰ or R ¹³ groups, wherein Z, R ¹⁰ and R ¹³ are as defined herein. As described in the document.

  As used herein, “alkoxy” refers to an —O-alkyl group. Examples of alkoxy groups include methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), t-butoxy groups, and the like.

  As used herein, “alkylthio” refers to an —S-alkyl group. Examples of the alkylthio group include methylthio, ethylthio, propylthio (for example, n-propylthio and isopropylthio), t-butylthio group, and the like.

As used herein, “haloalkyl” refers to an alkyl group having one or more halogen substituents. Examples of haloalkyl groups include CF ₃ , C ₂ F ₅ , CHF ₂ , CH ₂ F, CCl ₃ , CHCl ₂ , CH ₂ Cl, C ₂ Cl _{5 and the} like. Perhaloalkyl groups, ie, alkyl groups in which all of the hydrogen atoms are replaced with halogen atoms (eg, CF ₃ and C ₂ F ₅ ) are included in the definition of “haloalkyl”.

As used herein, “cycloalkyl” refers to non-aromatic carbocyclic groups including cyclized alkyl groups, cyclized alkenyl groups, and cyclized alkynyl groups. Cycloalkyl groups can be monocyclic (eg, cyclohexyl) or polycyclic (eg, including fused ring systems, bridged ring systems, and / or spiro ring systems), where the carbon atom is a ring Located inside or outside the system. Cycloalkyl groups generally have 3 to 14 ring atoms (eg, 3 to 8 carbon atoms in a monocyclic cycloalkyl group and 7 to 14 carbon atoms in a polycyclic cycloalkyl group). Atoms). It can be covalently linked to the defined chemical structure at any suitable ring position of the cycloalkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcalyl, adamantyl and spiro [4.5] decanyl Groups, homologues and isomers thereof, and the like. In some embodiments, cycloalkyl groups can be substituted with up to four independently selected —Z—R ¹⁰ or R ¹³ groups, wherein Z, R ¹⁰ and R ¹³ are As described in the specification. For example, a cycloalkyl group can include substitution of one or more oxo groups.

  As used herein, “heteroatom” refers to any atom (element) other than carbon or hydrogen, including, for example, nitrogen, oxygen, sulfur, phosphorus and selenium. Can be mentioned.

As used herein, “cycloheteroalkyl” includes at least one (eg, 1, 2, 3, 4 or 5) ring heteroatoms selected from O, N and S; And optionally refers to a non-aromatic cycloalkyl group containing one or more (eg, 1, 2 or 3) double or triple bonds. A cycloheteroalkyl group as a whole can have, for example, 3-14 ring atoms and 1-5 ring heteroatoms (eg, 3-6 for a monocyclic cycloheteroalkyl group). And 7 to 14 ring atoms for a polycyclic cycloheteroalkyl group. One or more N or S atoms in the cycloheteroalkyl ring may be oxidized (eg, morpholine N-oxide, thiomorpholine S-oxide, thiomorpholine S, S-dioxide). In some embodiments, the nitrogen atom of the cycloheteroalkyl group can have a substituent, such as a —Z—R ¹⁰ group or an R ¹³ group, where Z, R ^10, and R ¹³ are as defined herein. As described in the book. Cycloheteroalkyl groups also include one or more oxo groups (eg, phthalimidyl, piperidonyl, oxazolidinonyl, 2,4 (1H, 3H) -dioxo-pyrimidinyl, pyridine-2 (1H) -onyl, etc.). obtain. Examples of cycloheteroalkyl groups include morpholinyl, thiomorpholinyl, pyranyl, imidazolidinyl, imidazolinyl, oxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, among others. In some embodiments, the cycloheteroalkyl group can be optionally substituted with up to 4 independently selected —Z—R ¹⁰ or R ¹³ groups, wherein Z, R ¹⁰ and R ¹³ is as described herein.

  As used herein, “cyclic urea” means as part of a cycloheteroalkyl ring.

And a cycloheteroalkyl group that does not contain any other ring heteroatoms.

  As used herein, “cyclic carbamate” means as part of a cycloheteroalkyl ring.

And a cycloheteroalkyl group that does not contain any other ring heteroatoms.

  As used herein, “cyclic sulfinamide” means as part of a cycloheteroalkyl ring.

And a cycloheteroalkyl group that does not contain any other ring heteroatoms.

  As used herein, “cyclic sulfonamido” refers to a portion of a cycloheteroalkyl ring.

And a cycloheteroalkyl group that does not contain any other ring heteroatoms.

As used herein, “aryl” refers to an aromatic monocyclic hydrocarbon ring system or a polycyclic ring system, wherein at least one of the rings present in the ring system is An aromatic hydrocarbon ring, any other aromatic ring present in the ring system includes only hydrocarbons. In some embodiments, monocyclic aryl groups can have 6-14 carbon atoms and polycyclic aryl groups can have 8-14 carbon atoms. It can be covalently linked to the defined chemical structure at any suitable ring position of the aryl group. In some embodiments, aryl groups can have only aromatic carbocycles, such as phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl groups, and the like. In other embodiments, an aryl group is a polycyclic group in which at least one aromatic carbocycle is fused to one or more cycloalkyl or cycloheteroalkyl rings (ie, has a common bond with those rings). It can be a cyclic ring system. Examples of such aryl groups include, among others, benzo derivatives of cyclopentane (ie, indanyl groups that are 5,6-bicyclic cycloalkyl / aromatic ring systems), benzo derivatives of cyclohexane (ie, 6,6 -Bicyclic cycloalkyl / aromatic ring system tetrahydronaphthyl group), imidazoline benzo derivatives (ie 5,6-bicyclic cycloheteroalkyl / aromatic ring system benzimidazolinyl group) and pyran Benzo derivatives (ie 6,6-bicyclic cycloheteroalkyl / chromenyl groups which are aromatic ring systems). Other examples of aryl groups include benzodioxanyl, benzodioxolyl, chromanyl, indolinyl groups and the like. In some embodiments, the aryl group optionally comprises up to 4 independently selected —Z—R ¹⁰ or R ¹³ groups, wherein Z, R ¹⁰ and R ¹³ are As described herein.

  As used herein, “heteroaryl” refers to an aromatic monocyclic ring system comprising at least one ring heteroatom selected from oxygen (O), nitrogen (N) and sulfur (S), Or refers to a polycyclic ring system in which at least one of the rings present in the ring system is aromatic and contains at least one ring heteroatom. A heteroaryl group as a whole can have, for example, 5 to 13 ring atoms and can contain 1 to 5 ring heteroatoms. Heteroaryl groups include monocyclic heteroaryl rings fused to one or more aromatic carbocycles, non-aromatic carbocycles and non-aromatic cycloheteroalkyl rings. A heteroaryl group can be attached to the defined chemical structure at any heteroatom or carbon atom that results in a stable structure. Generally, heteroaryl rings do not contain O—O, S—S or S—O bonds. However, one or more N or S atoms in the heteroaryl group can be oxidized (eg, pyridine N-oxide, thiophene S-oxide, thiophene S, S-dioxide). Examples of heteroaryl groups include, for example, the 5-membered monocyclic and 5-6 bicyclic ring systems shown below:

Wherein T is O, S, NH, N—Z—R ² or N—Z—R ⁸ , where Z, R ² and R ⁸ are as defined herein. Examples of such heteroaryl rings include pyrrolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, thiadiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuryl , Benzothienyl, quinolyl, 2-methylquinolyl, isoquinolyl, quinoxalyl, quinazolyl, benzotriazolyl, benzimidazolyl, benzothiazolyl, benzoisothiazolyl, benzisoxazolyl, benzooxadiazolyl, benzoxazolyl, cinnolinyl, 1H -Indazolyl, 2H-indazolyl, indolizinyl, isobenzofuryl, naphthyridinyl, phthalazinyl, pteridi , Prynyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyridinyl, furopyridinyl, thienopyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl group, etc. Can be mentioned. Further examples of heteroaryl groups include 4,5,6,7-tetrahydroindolyl, tetrahydroquinolinyl, benzothienopyridinyl, benzofuropyridinyl groups and the like. In some embodiments, the heteroaryl group can be substituted with up to 4 substituents independently selected from the groups —Z—R ¹⁰ and —R ¹³ , wherein Z, R ¹⁰ and R ¹³ is as described in this specification.

The compounds of the present teachings can include a “divalent group” as defined herein as a linking group that can form a covalent bond with two other moieties. For example, the compounds described herein, divalent C _1-10 alkyl group, for example, include a methylene group.

At various places in the present specification, substituents of compounds are disclosed in groups or in ranges. The description is specifically intended to encompass each and every individual and partial combination of members of such groups and ranges. For example, the term “C _1-10 alkyl” includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁ -C ₁₀ , C _{1. -C 9, C 1 -C 8,} C 1 -C 7, C 1 -C 6, C 1 -C 5, C 1 -C 4, C 1 -C 3, C 1 -C 2, C 2 -C _{10, C 2 -C 9, C} 2 -C 8, C 2 -C 7, C 2 -C 6, C 2 -C 5, C 2 -C 4, C 2 -C 3, C 3 -C 10, _{C 3 -C 9, C 3 -C} 8, C 3 -C 7, C 3 -C 6, C 3 -C 5, C 3 -C 4, C 4 -C 10, C 4 -C 9, C 4 _{-C 8, C 4 -C 7,} C 4 -C 6, C 4 -C 5, C 5 -C 10, C 5 -C 9, C 5 -C 8, C 5 -C 7, C 5 -C ₆ , C ₆ -C ₁₀ , C ₆ -C ₉ C ₆ -C ₈ , C ₆ -C ₇ , C ₇ -C ₁₀ , C ₇ -C ₉ , C ₇ -C ₈ , C ₈ -C ₁₀ , C ₈ -C ₉ and C ₉ -C ₁₀ alkyl It is specifically intended to disclose separately. As another example, the term “5- to 13-membered heteroaryl group”

It is specifically intended to individually disclose heteroaryl groups having the following ring atoms; and the phrase “optionally substituted with 1 to 4 substituents” means 0, 1, 2, 3 4 pieces, 0-4 pieces, 0-3 pieces, 0-2 pieces, 0-1 pieces, 1-4 pieces, 1-3 pieces, 1-2 pieces, 2-4 pieces, 2-3 pieces and It is specifically intended to individually disclose chemical groups that may contain 3-4 substituents.

  The compounds described herein can contain asymmetric atoms (also called chiral centers), and some of these compounds can contain one or more asymmetric atoms or centers, thus providing optical isomerism. Forms (enantiomers) and diastereomers can occur. The present teachings describe such optical isomers (enantiomers) and diastereomers (geometric isomers) and racemic, resolved, enantiomerically pure (+) and (−) stereoisomers, and (+ ) And other mixtures of stereoisomers, as well as methods for preparing pharmaceutically acceptable salts thereof. In some embodiments, optical isomers can be obtained in enantiomerically enriched or pure form by standard procedures known to those skilled in the art, including, for example, chiral separation, Examples include diastereoisomeric salt formation, kinetic resolution and asymmetric synthesis. The present teachings also encompass methods for preparing cis and trans isomers of compounds containing alkenyl moieties (eg, alkenes and imines). The present teachings describe all methods for preparing regioisomers that may exist as pure forms and mixtures thereof (standard separation procedures known to those skilled in the art (eg, column chromatography, thin layer chromatography, simulated transfer) It is also understood to include bed chromatography and high performance liquid chromatography))).

  The compounds of the present teachings can be obtained from commercially available starting materials, compounds known in the literature or readily prepared intermediates using standard synthetic methods and procedures known to those skilled in the art: Can be prepared according to the procedure outlined in the scheme. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or standard textbooks in the field. Where typical process conditions or preferred process conditions (ie, reaction temperature, time, reactant molar ratio, solvent, pressure, etc.) are given, other process conditions may be used unless otherwise stated. It is understood that you can. Optimum reaction conditions may vary depending on the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Those skilled in the art of organic synthesis recognize that the nature and order of the proposed synthetic steps can be altered in order to optimize the formation of the compounds described herein.

The process described herein can be monitored according to any suitable method known in the art. For example, product formation may be performed by spectroscopic means (eg, nuclear magnetic resonance spectroscopy (eg, ¹ H or ¹³ C), infrared spectroscopy, spectrometry (eg, UV-visible light) or mass spectrometry. ) Or chromatography (eg, high performance liquid chromatography (HPLC) or thin layer chromatography).

  The preparation of compounds may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one skilled in the art. Protecting group chemistry is described, for example, in Greene et al., Protective Groups in Organic Synthesis, 4th Ed. , Wiley & Sons, 2006, the entire disclosure of which is incorporated herein by reference for all purposes.

  The reactions of the processes described herein can be performed in a suitable solvent that can be readily selected by one skilled in the art of organic synthesis. A suitable solvent is typically substantially non-reactive with the reactants, intermediates and / or products at the temperature at which the reaction is carried out, i.e., at a temperature that can range from the melting point of the solvent to the boiling point of the solvent. It is reactive. A given reaction can be carried out in one solvent or a mixture of two or more solvents. Depending on the particular reaction step, a suitable solvent for the appropriate reaction step can be selected.

  Scheme 1 below shows an exemplary synthetic route for preparing compounds of formula I.

As shown in Scheme 1, compounds of formula I, including compound iv, can be prepared from sulfonyl chloride intermediate i. The compound of formula ii can be obtained by reacting the compound of formula i with an amino acid or derivative thereof. The —NO ₂ group can be converted to an amino group, whereby R ² and R ³ can be incorporated to give compounds of formula iv.

  Scheme 2 below shows an exemplary synthetic route for preparing sulfonyl chloride intermediate i.

As shown in Scheme 2, a compound having a tricyclic core optionally substituted with R ⁴ and R ⁵ , ie, a compound of formula v, is nitrated to provide a compound of formula vi. And the compound of formula i is obtained by direct sulfonation of the compound or indirectly the compound of formula ix. By further nitration of the compound of formula ix, the compound of formula i can be obtained. Alternatively, a compound of formula v can be converted to a compound of formula i by nitration followed by chlorosulfonation.

  The following examples illustrate various synthetic routes that can be used to prepare compounds of the invention of formula I.

Example 1: Preparation of (R) -2- (7-methoxycarbonylamino-dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid Step 1: Preparation of 3-nitrodibenzo [b, d] furan The following procedure Keumi et al. (1991), J. et al. Org. Chem. , 56: 4671-4677. Dibenzofuran (50 g) was mixed with 400 mL of trifluoroacetic acid (TFA). The resulting suspension was cooled in an ethanol ice bath and 11.7 mL of fuming nitric acid (HNO ₃ ,> 90%) was added dropwise over 10 minutes. The reaction mixture was warmed to room temperature, stirred for 2 hours and then filtered. The solid obtained from filtration was triturated with methanol (MeOH) and dried under reduced pressure to give 45 g of 3-nitrodibenzo [b, d] furan in 70% yield.

Step 2: Preparation of 7-nitrodibenzo [b, d] furan-2-sulfonic acid Circle containing 3-nitrodibenzo [b, d] furan (21.4 g, 100 mmol) in 200 mL of chloroform (CHCl ₃ ). To the bottom flask, 0 ° C. chlorosulfonic acid (15.2 g, 130 mmol) was slowly added. The resulting suspension was warmed to room temperature and stirred for 4 hours. After cooling to 0 ° C., the reaction mixture was filtered and 24.1 g of 7-nitrodibenzo [b, d] furan-2-sulfonic acid was recovered from the filtrate as a white solid in 81% yield.

Step 3: Preparation of 7-nitrodibenzo [b, d] furan-2-sulfonyl chloride 15 mL of 7-nitrodibenzo [b, d] furan-2-sulfonic acid (2.93 g, 10 mmol) obtained from Step 2 After mixing with thionyl chloride (SOCl ₂ ), a few drops of dimethylformamide (DMF) were added slowly. The mixture was stirred at 80 ° C. for 24 hours. The reaction mixture was filtered and excess SOCl ₂ in the filtrate was removed under reduced pressure. The crude product from the filtrate was isolated as a solid and triturated with ice water to give 2.78 g of 7-nitrodibenzo [b, d] furan-2-sulfonyl chloride as an off-white solid in 89% yield. It was.

Step 4: Preparation of (R) -tert-butyl 3-methyl-2- (7-nitrodibenzo [b, d] furan-2-sulfonamido) butanoate 7-nitrodibenzo [b, d] furan from Step 3 2-sulfonyl chloride (570 mg, 1.83 mmol) and (R) -tert-butyl 2-amino-3-methylbutanoate hydrochloride (422 mg, 2.0 mmol) with 5 mL of dichloromethane (CH ₂ Cl ₂ ). After mixing, 0 ° C. N, N-diisopropylethylamine (520 mg, 4 mmol) was slowly added. The mixture was stirred and allowed to warm to room temperature over 4 hours. The reaction mixture was purified by column chromatography to give (R) -valinesulfonamide as a white solid in 88% yield.

Step 5: Preparation of (R) -tert-butyl 2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate Nitrosulfonamide obtained in step 4 (480 mg) Was mixed with 20 mL MeOH and 100 mg palladium on carbon (Pd / C) (10%). The reaction was performed in a Parr shaker at room temperature overnight under hydrogen (50 psi). The reaction mixture is filtered through Celite® and concentrated to give (R) -tert-butyl 2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate. (430 mg) was obtained as an off-white solid in quantitative yield.

Step 6: Preparation of (R) -tert-butyl 2- (7-methoxycarbonylamino-dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid Arylamine from step 5 (0.25 mmol) and dimethylaminopyridine ( DMAP, 37 mg, 0.3 mmol) was dissolved in ₂ mL of CH ₂ Cl ₂ and then methyl chloroformate (0.28 mmol) was added. The mixture was stirred at room temperature overnight and purified by silica gel column chromatography to give (R) -tert-butyl 2- (7-methoxycarbonylamino-dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid as a white solid As a 90% yield.

Step 7: Preparation of (R) -2- (7-methoxycarbonylamino-dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid Sulfonamide t-butyl ester (0.2 mmol) from Step 6 was added to 2 mL of TFA. Dissolved in / CH ₂ Cl ₂ (1: 1). The solution was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was triturated in acetonitrile (CH ₃ CN) / water (H ₂ O) followed by a lyophilization process. (S) -2- (7-methoxycarbonylamino-dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid was obtained as a white solid. ^{_{HRMS: - [C 19 H 20}} N 2 O 7 S-H] calcd 419.09185 for; found ^{(ESI-FTMS, [M-} H] 1-) 419.0916.

  The sodium salt was prepared by treating (S) -2- (7-methoxycarbonylamino-dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid with 1.0 equivalent of sodium hydroxide (NaOH). The salt was obtained as a white solid.

Example 2: Preparation of (R) -3-methyl-2- (7- (propoxycarbonylamino) dibenzo [b, d] furan-2-sulfonamido) butanoic acid Analogous to the procedure described in Example 1 According to the procedure, (R) -3-methyl-2- (7- (propoxycarbonylamino) dibenzo [b, d] furan-2-sulfonamido) butanoic acid was converted to (R) -tert using propyl chloroformate. Prepared from -butyl 2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate and obtained as a white solid. ^{_{HRMS: - [C 21 H 24}} N 2 O 7 S-H] calcd 448.1304 for; found ^{(ESI-FTMS, [M-} H] 1-) 448.1313.

Example 3: Preparation of (R) -2- (7- (isopropoxycarbonylamino) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid Analogous to the procedure described in Example 1 According to the procedure, (R) -2- (7- (isopropoxycarbonylamino) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid was converted to (R) -tert using isopropyl chloroformate. Prepared from -butyl 2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate and obtained as a white solid. ^{_{HRMS: - [C 21 H 24}} N 2 O 7 S-H] calcd 447.1226 for; found ^{(ESI-FTMS, [M-} H] 1-) 447.1216.

Example 4: Preparation of (R) -3-methyl-2- (7- (phenoxycarbonylamino) dibenzo [b, d] furan-2-sulfonamido) butanoic acid Analogous to the procedure described in Example 1 According to the procedure, using phenoxychloroformate, (R) -3-methyl-2- (7- (phenoxycarbonylamino) dibenzo [b, d] furan-2-sulfonamido) butanoic acid is converted to (R)- Prepared from tert-butyl 2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate and obtained as a white solid. ^{_{HRMS: - [C 24 H 22}} N 2 O 7 S-H] calcd 481.1069 for; found ^{(ESI-FTMS, [M-} H] 1-) 481.1153.

Example 5: Preparation of (R) -2- (7- (3-ethylureido) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid Step 1: (R) -tert-Butyl 2 Preparation of-(7- (3-ethylureido) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate (R) -2- (7-amino-dibenzofuran-2-sulfonylamino) -3-Methyl-butyric acid tert-butyl ester (138 mg, 0.33 mmol) and ethyl isocyanate (0.4 mmol) were mixed with 2 mL of tetrahydrofuran (THF). The mixture was irradiated with microwaves at 120 ° C. for 20 minutes. After being subjected to column chromatography, (R) -tert-butyl 2- (7- (3-ethylureido) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate was converted to an off-white solid. As a 75% yield.

Step 2: Preparation of (R) -2- (7- (3-ethylureido) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid (R) -tert-butyl 2- (7- (3-Ethylureido) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate (0.2 mmol) was dissolved in 4 mL of TFA / CH ₂ Cl ₂ (1: 1). The solution was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue was triturated with ether. After drying under high vacuum, (R) -2- (7- (3-ethylureido) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid was obtained as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.81 (dd, J = 13.90, 6.82 Hz, 6H), 1.08 (t, 3H), 1.88-1.99 (m , 1H), 3.09-3.20 (m, 2H), 3.58 (dd, J = 9.60, 6.06 Hz, 1H), 6.25 (t, J = 5.56 Hz, 1H) , 7.23 (dd, J = 8.59, 1.77 Hz, 1H), 7.75-7.80 (m, 1H), 7.80-7.84 (m, 1H), 8.00 ( d, J = 9.60 Hz, 1H), 8.07 (dd, J = 5.31, 3.03 Hz, 2H), 8.42 (dd, J = 1.89, 0.63 Hz, 1H), 8 .87 (s, 1H) and 12.50 (s, 1H) (extra peak at 3.67); MS (ES-): 432.1.

  The sodium salt was prepared by treating (R) -2- (7- (3-ethylureido) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid with 1.0 equivalent of NaOH. . The salt was obtained as a white solid.

Example 6: Preparation of (R) -2- {7- [3- (4-Fluoro-benzyl) -ureido] -dibenzofuran-2-sulfonylamino} -3-methyl-butyric acid Procedure described in Example 5 According to a procedure similar to that described above, using 4-fluoro-benzyl isocyanate, (R) -2- {7- [3- (4-fluoro-benzyl) -ureido] -dibenzofuran-2-sulfonylamino} -3- Methyl-butyric acid was prepared as a white solid from (R) -tert-butyl 2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate. MS (ES-): 512.1.

Example 7: Preparation of (R) -2- [7- (3-cyclopentylmethyl-ureido) -dibenzofuran-2-sulfonylamino] -3-methyl-butyric acid Following a procedure similar to that described in Example 5 , (R) -2- [7- (3-cyclopentylmethyl-ureido) -dibenzofuran-2-sulfonylamino] -3-methyl-butyric acid as an off-white solid using (R)- Prepared from tert-butyl 2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.81 (dd, J = 14.15, 6.82 Hz, 6H), 1.33-1.45 (m, 2H), 1.50-1 .71 (m, 4H), 1.80-2.00 (m, 3H), 3.58 (dd, J = 9.47, 5.94 Hz, 1H), 3.91-4.04 (m, 1H), 6.31 (d, J = 7.33 Hz, 1H), 7.20 (dd, J = 8.59, 1.77 Hz, 1H), 7.75-7.87 (m, 2H), 8.01 (d, J = 9.35 Hz, 1H), 8.04-8.11 (m, 2H), 8.42 (d, J = 1.52 Hz, 1H) and 8.71 (s, 1H) ) 12.50 (s, 1H); MS (ES-) 472.1.

Example 8: Preparation of (R) -2- [7- (3-Isopropylureido) -dibenzofuran-2-sulfonylamino] -3-methyl-butyric acid Following a procedure similar to that described in Example 5, isocyanide (R) -2- [7- (3-Isopropylureido) -dibenzofuran-2-sulfonylamino] -3-methyl-butyric acid as an off-white solid using isopropyl acid (R) -tert-butyl 2 Prepared from-(7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.81 (dd, J = 14.15, 6.82 Hz, 6H), 1.12 (s, 3H), 1.13 (s, 3H), 1.89-1.99 (m, 1H), 3.58 (dd, J = 9.47, 5.94 Hz, 1H), 3.80 (dd, J = 13.89, 6.57 Hz, 1H) 6.15 (d, J = 7.58 Hz, 1H), 7.20 (dd, J = 8.59, 1.77 Hz, 1H), 7.75-7.85 (m, 2H), 8. 01 (d, J = 9.60 Hz, 1H), 8.05-8.10 (m, 2H), 8.42 (d, J = 2.02 Hz, 1H) and 8.74 (s, 1H) 12 .50 (s, 1 H); MS (ES-) 446.1.

Example 9: Preparation of (R) -3-methyl-2- {7- [3- (3,4,5-trimethoxy-phenyl) -ureido] -dibenzofuran-2-sulfonylamino} -butyric acid Following procedures similar to those described, using 3,4,5-trimethoxy-phenyl isocyanate, (R) -3-methyl-2- {7- [3- (3,4,5-trimethoxy- (Phenyl) -ureido] -dibenzofuran-2-sulfonylamino} -butyric acid as an off-white solid (R) -tert-butyl 2- (7-aminodibenzo [b, d] furan-2-sulfonamide) -3- Prepared from methyl butanoate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.82 (dd, J = 14.15, 6.82 Hz, 6H), 1.95 (dd, J = 12.88, 6.82 Hz, 1H) , 3.56-3.62 (m, 1H), 3.62 (s, 3H), 3.77 (s, 6H), 6.83 (s, 2H), 7.33 (dd, J = 8 .46, 1.89 Hz, 1H), 7.79-7.83 (m, 1H), 7.83-7.88 (m, 1H), 8.02 (d, J = 9.60 Hz, 1H) , 8.09 (d, J = 1.77 Hz, 1H), 8.15 (d, J = 8.34 Hz, 1H), 8.47 (dd, J = 1.77, 0.51 Hz, 1H), 8.76 (s, 1H), 9.06 (s, 1H) and 12.50 (s, 1H); MS (ES-): 570.1.

Example 10: Preparation of (R) -2- (7- (3- (3,4-difluorophenyl) ureido) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid (R) -2- (7- (3- (3,4-difluorophenyl) ureido) dibenzo [b, d] using 3,4-difluorophenyl isocyanate following a procedure similar to that described. Furan-2-sulfonamido) -3-methylbutanoic acid as an off-white solid (R) -tert-butyl 2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutano Prepared from ate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.82 (dd, J = 13.77, 6.69 Hz, 6H), 1.89-2.01 (m, 1H), 3.60 (dd , J = 9.47, 5.94 Hz, 1H), 7.14-7.21 (m, 1H), 7.33-7.42 (m, 2H), 7.66-7.74 (m, 1H), 7.79-7.84 (m, 1H), 7.84-7.88 (m, 1H), 8.03 (d, J = 9.60 Hz, 1H), 8.09 (d, J = 1.77 Hz, 1H), 8.16 (d, J = 8.34 Hz, 1H), 8.48 (d, J = 2.02 Hz, 1H), 9.06 (s, 1H), 9. 22 (s, 1H) and 12.50 (s, 1H); MS (ES-) 516.1.

Example 11: Preparation of (R) -2- (7- (3- (4- (dimethylamino) phenyl) ureido) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid According to a procedure similar to that described in Example 1, using 4- (dimethylamino) phenyl isocyanate, (R) -2- (7- (3- (4- (dimethylamino) phenyl) ureido) dibenzo [b , D] furan-2-sulfonamido) -3-methylbutanoic acid as an off-white solid (R) -tert-butyl 2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3- Prepared from methyl butanoate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.82 (dd, J = 13.90, 6.82 Hz, 6H), 1.87-2.01 (m, 1H), 3.02 (s , 6H), 3.59 (dd, J = 9.47, 5.94 Hz, 1H), 7.18 (s, 2H), 7.34 (dd, J = 8.46, 1.64 Hz, 1H) , 7.49 (d, J = 8.59 Hz, 2H), 7.77-7.88 (m, 2H), 8.03 (d, J = 9.60 Hz, 1H), 8.09-8. 19 (m, 2H), 8.47 (d, J = 1.77 Hz, 1H), 8.97 (s, 1H), 9.29 (s, 1H) and 12.50 (s, 1H); MS (ES-) 523.2.

Example 12: Preparation of (R) -3-methyl-2- (7- (3- (3-phenoxyphenyl) ureido) dibenzo [b, d] furan-2-sulfonamido) -butanoic acid Following a procedure similar to that described, using 3-phenoxyphenyl isocyanate and using (R) -3-methyl-2- (7- (3- (3-phenoxyphenyl) ureido) dibenzo [b, d] Furan-2-sulfonamido) -butanoic acid as an off-white solid from (R) -tert-butyl 2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate Prepared. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.82 (dd, J = 14.02, 6.69 Hz, 6H), 1.89-2.00 (m, 1H), 3.59 (dd , J = 9.60, 6.06 Hz, 1H), 6.62-6.67 (m, 1H), 7.03-7.08 (m, 2H), 7.14-7.20 (m, 2H), 7.27-7.33 (m, 3H), 7.39-7.45 (m, 2H), 7.79-7.83 (m, 1H), 7.83-7.87 ( m, 1H), 8.02 (d, J = 9.35 Hz, 1H), 8.06 (d, J = 1.77 Hz, 1H), 8.14 (d, J = 8.59 Hz, 1H), 8.47 (d, J = 1.26 Hz, 1H), 8.94 (s, 1H), 9.09 (s, 1H) and 12.50 (s, 1H); MS (ES−) 57 .2.

Example 13: Preparation of (R) -3-methyl-2- (7-ureidodibenzo [b, d] furan-2-sulfonamido) butanoic acid According to a procedure analogous to that described in Example 5, R) -3-methyl-2- (7-ureidodibenzo [b, d] furan-2-sulfonamido) butanoic acid as an off-white solid (R) -tert-butyl 2- (7-aminodibenzo [b , D] furan-2-sulfonamido) -3-methylbutanoate and 4-methoxybenzyl isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.82 (dd, J = 14.02, 6.69 Hz, 6H), 1.89-1.99 (m, 1H), 3.59 (dd , J = 9.47, 5.94 Hz, 1H), 6.02 (s, 2H), 7.25 (dd, J = 8.46, 1.89 Hz, 1H), 7.76-7.80 ( m, 1H), 7.80-7.85 (m, 1H), 8.01 (d, J = 9.35 Hz, 1H), 8.04-8.11 (m, 2H), 8.43 ( d, J = 2.02 Hz, 1H), 8.97 (s, 1H) and 12.50 (s, 1H); MS (ES-) 404.1.

Example 14: Preparation of (R) -3-methyl-2- (7- (3- (4- (trifluoromethoxy) phenyl) ureido) dibenzo [b, d] furan-2-sulfonamido) butanoic acid Following a procedure similar to that described in Example 5, using 4- (trifluoromethoxy) phenyl isocyanate, (R) -3-methyl-2- (7- (3- (4- (trifluoromethoxy ) Phenyl) ureido) dibenzo [b, d] furan-2-sulfonamido) butanoic acid as off-white solid (R) -tert-butyl 2- (7-aminodibenzo [b, d] furan-2-sulfone Prepared from (amido) -3-methylbutanoate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.82 (dd, J = 13.90, 6.57 Hz, 6H), 1.90-2.00 (m, 1H), 3.60 (dd , J = 9.47, 5.94 Hz, 1H), 7.28-7.38 (m, 3H), 7.57-7.63 (m, 2H), 7.79-7.84 (m, 1H), 7.84-7.88 (m, 1H), 8.03 (d, J = 9.60 Hz, 1H), 8.11 (d, J = 1.77 Hz, 1H), 8.16 ( d, J = 8.59 Hz, 1H), 8.48 (dd, J = 2.02, 0.51 Hz, 1H), 9.03 (s, 1H), 9.18 (s, 1H) and 12. 51 (s, 1 H); MS (ES-) 564.1.

Example 15: Preparation of (R) -2- (7- (3- (2,6-dichloropyridin-4-yl) ureido) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid Following a procedure similar to that described in Example 5, using 2,6-dichloropyridin-4-yl isocyanate, (R) -2- (7- (3- (2,6-dichloropyridine- 4-yl) ureido) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid as an off-white solid (R) -tert-butyl 2- (7-aminodibenzo [b, d] furan 2-sulfonamido) -3-methylbutanoate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.82 (dd, J = 13.64, 6.82 Hz, 6H), 1.90-2.00 (m, 1H), 3.60 (dd , J = 9.47, 5.94 Hz, 1H), 7.40 (dd, J = 8.59, 1.77 Hz, 1H), 7.60 (s, 2H), 7.82-7.86 ( m, 1H), 7.86-7.90 (m, 1H), 8.04 (d, J = 9.60 Hz, 1H), 8.08 (d, J = 1.77 Hz, 1H), 8. 21 (d, J = 8.34 Hz, 1H), 8.50 (dd, J = 1.77, 0.51 Hz, 1H), 9.60 (s, 1H), 9.71 (s, 1H) and 12.50 (s, 1 H); MS (ES-) 549.1.

Example 16: (R) -3-Methyl-2- (7- (3- (2- (thiophen-2-yl) ethyl) ureido) dibenzo [b, d] furan-2-sulfonamido) butanoic acid Preparation Following a procedure similar to that described in Example 5, using 2- (thiophen-2-yl) ethyl isocyanate, (R) -3-methyl-2- (7- (3- (2- (Thiophen-2-yl) ethyl) ureido) dibenzo [b, d] furan-2-sulfonamido) butanoic acid as an off-white solid (R) -tert-butyl 2- (7-aminodibenzo [b, d It was prepared from furan-2-sulfonamido) -3-methylbutanoate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.82 (dd, J = 13.90, 6.82 Hz, 6H), 1.89-1.99 (m, 1H), 3.00 (t , J = 6.95 Hz, 2H), 3.37-3.43 (m, 2H), 3.59 (dd, J = 9.47, 5.94 Hz, 1H), 6.37 (t, J = 5.81 Hz, 1H), 6.94 (dd, J = 3.41, 1.14 Hz, 1H), 6.99 (dd, J = 5.05, 3.28 Hz, 1H), 7.23 (dd , J = 8.59, 1.77 Hz, 1H), 7.36 (dd, J = 5.05, 1.26 Hz, 1H), 7.77-7.81 (m, 1H), 7.81−. 7.85 (m, 1H), 8.01 (d, J = 9.60 Hz, 1H), 8.08 (dd, J = 5.05, 3.03 Hz, 2H) 8.43 (dd, J = 1.90,0.63Hz, 1H), 9.01 (s, 1H) and 12.50 (s, 1H); MS (ES-) 514.2.

Example 17: Preparation of (S) -2- (7- (3-ethylureido) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid Analogous to the procedure described in Example 5 According to the procedure, (S) -2- (7- (3-ethylureido) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid as an off-white solid (S) -tert-butyl 2 Prepared from-(7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.82 (dd, J = 13.90, 6.82 Hz, 6H), 1.08 (t, J = 7.20 Hz, 3H), 1.89 -1.99 (m, 1H), 3.10-3.19 (m, 2H), 3.58 (dd, J = 9.47, 5.94 Hz, 1H), 6.25 (t, J = 5.56 Hz, 1H), 7.23 (dd, J = 8.59, 1.77 Hz, 1H), 7.76-7.80 (m, 1H), 7.80-7.85 (m, 1H) ), 8.01 (d, J = 9.60 Hz, 1H), 8.07 (dd, J = 0.05, 3.03 Hz, 2H), 8.42 (dd, J = 1.89, 0. 0). 63 Hz, 1H), 8.88 (s, 1H) and 12.50 (s, 1H); MS (ES-) 432.1.

Example 18: Preparation of (R) -3-methyl-2- (7- (methylsulfonamido) dibenzo [b, d] furan-2-sulfonamido) butanoic acid Step 1: (R) -3-methyl- Preparation of 2- (7- (methylsulfonamido) dibenzo [b, d] furan-2-sulfonamido) butanoic acid tert-butyl ester (R) -tert-butyl 2- (7-aminodibenzo [b, d] Furan-2-sulfonamido) -3-methylbutanoate (0.36 mmol) and DMAP (53 mg, 0.43 mmol) were mixed with ₂ mL of CH ₂ Cl ₂ and then methylsulfonyl chloride (0.40 mmol) was added. It was. The mixture was stirred at room temperature for 2 hours and purified by silica gel column chromatography to obtain methylsulfonamide t-butyl ester as a white solid in 90% yield.

Step 2: Preparation of (R) -3-methyl-2- (7- (methylsulfonamido) dibenzo [b, d] furan-2-sulfonamido) butanoic acid The sulfonamide t-butyl ester was added to 4 mL of TFA / Dissolved in CH ₂ Cl ₂ (1: 1). The solution was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue was triturated in CH ₃ CN / H ₂ O followed by a lyophilization process. (R) -3-Methyl-2- (7- (methylsulfonamido) dibenzo [b, d] furan-2-sulfonamido) butanoic acid was obtained as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.81 (dd, J = 14.15, 6.82 Hz, 6H), 1.94 (dd, J = 12.88, 6.82 Hz, 1H) 3.09 (s, 3H), 3.59 (dd, J = 9.47, 5.94 Hz, 1H), 7.29 (dd, J = 8.46, 1.89 Hz, 1H), 7. 57 (d, J = 1.77 Hz, 1H), 7.82-7.86 (m, 1H), 7.87-7.90 (m, 1H), 8.05 (d, J = 9.60 Hz) , 1H), 8.24 (d, J = 8.34 Hz, 1H), 8.51 (dd, J = 2.02, 0.51 Hz, 1H), 10.18 (s, 1H) and 12.50. _{(s, 1H); HRMS:} 2 [C 18 H 20 N 2 O 7 S 2 + H] calculated for ⁺ 881.14966; real Measurement (ESI-FTMS, [2M + H] ¹⁺ ) 881.1488.

  The sodium salt was prepared by treating (R) -3-methyl-2- (7- (methylsulfonamido) dibenzo [b, d] furan-2-sulfonamido) butanoic acid with 1.0 equivalent of NaOH. . The salt was obtained as a white solid.

Example 19: Preparation of (S) -3-methyl-2- (7- (methylsulfonamido) dibenzo [b, d] furan-2-sulfonamido) butanoic acid Analogous to the procedure described in Example 18 (S) -3-Methyl-2- (7- (methylsulfonamido) dibenzo [b, d] furan-2-sulfonamide) using the corresponding aniline analog obtained from L-valine according to the procedure Butanoic acid was prepared as a white solid. MS (ES-) 439.1.

Example 20: Preparation of (R) -2- (7- (chloromethylsulfonamido) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid Analogous to the procedure described in Example 18 According to the procedure, using chloromethylsulfonyl chloride, (R) -2- (7- (chloromethylsulfonamido) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid as a white solid ( Prepared in 95% yield from R) -tert-butyl 2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate. MS (ES-) 473.0.

Example 21: Preparation of (R) -3-methyl-2- (7- (isopropylsulfonamido) dibenzo [b, d] furan-2-sulfonamido) butanoic acid Analogous to the procedure described in Example 18 According to the procedure, (R) -3-methyl-2- (7- (isopropylsulfonamido) dibenzo [b, d] furan-2-sulfonamido) butanoic acid was converted to (R) -tert using isopropylsulfonyl chloride. Prepared from -butyl 2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate. MS (ES-) 467.1.

Example 22: Preparation of (R) -2- (7- (3,5-dimethylisoxazole-4-sulfonamido) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid (R) -2- (7- (3,5-dimethylisoxazole-4-sulfone) using 3,5-dimethylisoxazol-4-ylsulfonyl chloride according to a procedure similar to that described in Amido) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid as a white solid (R) -tert-butyl 2- (7-aminodibenzo [b, d] furan-2-sulfonamide) Prepared from -3-methylbutanoate. MS (ES-) 520.1.

Example 23: Preparation of (R) -3-methyl-2- (7- (phenylsulfonamido) dibenzo [b, d] furan-2-sulfonamido) butanoic acid Analogous to the procedure described in Example 18 According to the procedure, using phenylsulfonyl chloride, (R) -3-methyl-2- (7- (phenylsulfonamido) dibenzo [b, d] furan-2-sulfonamido) butanoic acid as a white solid (R ) -Tert-butyl 2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate. MS (ES-) 501.1.

Example 24: Preparation of (S) -2- (7- (methoxycarbonylamino) dibenzo [b, d] thiophene-2-sulfonamido) -3-methylbutanoic acid A procedure similar to that described in Example 1 According to (S) -2- (7- (methoxycarbonylamino) dibenzo [b, d] thiophene-2-butyrate using (S) -tert-butyl 2-amino-3-methylbutanoate hydrochloride Sulfonamido) -3-methylbutanoic acid was prepared from dibenzothiophene as a white solid. _{HRMS: [C 19 H 20 N} 2 O 6 S 2 + H] + calcd 437.08355 for; found ^{(ESI-FTMS, [M +} H] 1+) 437.0833.

Example 25: Preparation of (R) -2- (7- (methoxycarbonylamino) dibenzo [b, d] thiophene-2-sulfonamido) -3-methylbutanoic acid A procedure similar to that described in Example 1 In accordance with (R) -tert-butyl 2-amino-3-methylbutanoate hydrochloride using (R) -2- (7- (methoxycarbonylamino) dibenzo [b, d] thiophene-2- Sulfonamido) -3-methylbutanoic acid was prepared from dibenzothiophene as a white solid. _{HRMS: [C 19 H 20 N} 2 O 6 S 2 + H] + calcd 437.08355 for; found ^{(ESI-FTMS, [M +} H] 1+) 437.0833.

Example 26: Preparation of (S) -3-methyl-2- (7- (methylsulfonamido) dibenzo [b, d] thiophene-2-sulfonamido) butanoic acid Analogous to the procedure described in Example 18 According to the procedure, (S) -3-methyl-2- (7- (methylsulfonamido) dibenzo [b, d] thiophene-2-sulfonamido) butanoic acid as a white solid (S) -tert-butyl 2- ( Prepared from 7-aminodibenzo [b, d] thiophene-2-sulfonamido) -3-methylbutanoate. _{HRMS: [C 18 H 20 N} 2 O 6 S 3 + H] + calcd 457.05562 for; found ^{(ESI-FTMS, [M +} H] 1+) 457.0555.

Example 27: Preparation of (R) -3-methyl-2- (7- (methylsulfonamido) dibenzo [b, d] thiophene-2-sulfonamido) butanoic acid Analogous to the procedure described in Example 18 According to the procedure, (R) -3-methyl-2- (7- (methylsulfonamido) dibenzo [b, d] thiophene-2-sulfonamido) butanoic acid was converted to (R) -tert-butyl 2- (7-amino) Prepared from dibenzo [b, d] thiophene-2-sulfonamido) -3-methylbutanoate and obtained as a white solid. _{HRMS: [C 18 H 20 N} 2 O 6 S 3 + H] + calcd 457.05562 for; found ^{(ESI-FTMS, [M +} H] 1+) 457.0548.

Example 28: Preparation of (S) -2- (8- (isobutoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Step 1: Dibenzo [b, d] furan- Preparation of 3-amine 3-Nitrodibenzo [b, d] furan obtained from nitration of dibenzofuran (Example 1) (2.13 g, 10 mmol) was mixed with 20 mL MeOH and 0.5 g Pd / C. . The reaction was carried out under a hydrogen (50 psi) overnight using a Parr shaker at room temperature. The reaction mixture was filtered through Celite®. Removal of MeOH gave 1.80 g of dibenzo [b, d] furan-3-amine as an off-white solid in 98% yield.

Step 2: Preparation of dibenzo [b, d] furan-3-sulfonyl chloride Dibenzo [b, d] furan-3-amine (6 g, 32.4 mmol), glacial acetic acid (AcOH, 60 mL) and concentrated hydrochloric acid (HCl, 60 mL) ) Was added slowly to sodium nitrite (NaNO ₂ ) (2.68 g, 38.8 mmol) in 20 mL of H ₂ O at −20 ° C. to give a yellow suspension. The suspension was stirred for 30 min, followed by sulfur dioxide (30 mL) and copper (I) chloride dihydrate (CuCl ₂ -2H ₂ O, 11.5 g, 676.2 mmol in 40 mL 50% AcOH. ) At a temperature of -23 ° C. The mixture was slowly warmed to room temperature and stirred for 21 hours. When the disappearance of starting material was confirmed by thin layer chromatography (TLC), the reaction mixture was quenched with water and extracted with ethyl acetate (EtOAc, 3 × 50 mL). The combined organic layers were washed with a saturated solution of sodium bicarbonate and brine, dried over sodium sulfate, and concentrated to give 4.44 g of dibenzo [b, d] furan-3-sulfonyl chloride as a white solid. % Yield.

Step 3: dissolving 8-nitro dibenzo [b, d] furan-3-sulfonyl chloride prepared dibenzo [b, d] furan-3-sulfonyl chloride (10.64 g, 40 mmol) and of _CH 2 Cl ₂ 60 mL, The resulting solution was stirred at room temperature for 30 minutes. After adding 100 mL of TFA to the solution, nitric acid (HNO ₃ , 10.6 g, 168 mmol) was added dropwise. The mixture was stirred at room temperature for 6 hours and monitored by ¹ H NMR to precipitate the desired product from the reaction mixture. CH ₂ Cl ₂ was removed under reduced pressure, more TFA (60 mL) was added, and the reaction mixture was filtered. The filter cake was washed with cold water to give 10.11 g of 8-nitrodibenzo [b, d] furan-3-sulfonyl chloride as a yellow solid in 78% yield.

Step 4: Preparation of (S) -tert-butyl 3-methyl-2- (8-nitrodibenzo [b, d] furan-3-sulfonamido) butanoate L-valine t-butyl ester (HCl salt, 14.98 g , 71.4 mmol) and di - isopropylethylamine (20 g, and 24.9 mL) were combined in _{CH 2 Cl 2 (250mL),} 8- nitro dibenzo [b, d] from step 3 furan-3-sulfonyl chloride ( 22.26 g, 71.4 mmol) was added slowly at 0 ° C. The reaction was warmed to room temperature over 2 hours. Water (200 mL) was added to the reaction flask and CH ₂ Cl ₂ was removed under reduced pressure with continued stirring. After complete removal of CH ₂ Cl ₂ , the desired product precipitated as a white solid in the aqueous medium. The suspension is filtered and the filter cake is washed with water and dried to give 30.4 g of (S) -tert-butyl 3-methyl-2- (8-nitrodibenzo [b, d] furan-3. -Sulphonamido) butanoate was obtained in 94% yield.

Step 5: Preparation of (S) -tert-butyl 2- (8-aminodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (S) -tert- in MeOH (150 mL) Butyl 3-methyl-2- (8-nitrodibenzo [b, d] furan-3-sulfonamido) butanoate (6.12 g) and 0.6 g of 10% Pd / C (50% water) under a hydrogen atmosphere ( 50 psi) in a Parr shaker for 6 hours. The suspension was filtered through Celite®. The filtrate was concentrated to give 98% of 5.70 g of (S) -tert-butyl 2- (8-aminodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate as a white solid. The yield was obtained.

Step 6: Preparation of (S) -2- (8- (isobutoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid tert-butyl ester (S)-from Step 5 tert- butyl 2- (8-amino-dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (0.5 mmol) and dissolved DMAP a (0.6 mmol) of _CH 2 Cl ₂ 5mL After that, isobutyl chloroformate (0.55 mmol) was added slowly. The mixture was stirred overnight at room temperature and purified by silica gel column chromatography to give (S) -2- (8- (isobutoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutane. The acid tert-butyl ester was obtained as a white solid in 85% yield.

Step 7: Preparation of (S) -2- (8- (isobutoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Carbamate t-butyl ester (0.4 mmol, Step 6) ) Was dissolved in 4 mL TFA / CH ₂ Cl ₂ (1: 1). The solution was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was triturated in CH ₃ CN / water followed by a lyophilization process. (S) -2- (8- (isobutoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid was obtained as a white solid in 98% yield. _{HRMS: [C 22 H 26 N} 2 O 7 S + H] + calcd 463.15335 for; found ^{(ESI-FTMS, [M +} H] 1+) 463.1544.

  The sodium salt was prepared by treating (S) -2- (8- (isobutoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid with 1.0 equivalent of NaOH. . The salt was obtained as a white solid.

Example 29: Preparation of (S) -2- (8-((2-chloroethoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid described in Example 28 According to a procedure similar to that of (S) -2- (8-((2-chloroethoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid as a white solid, 100% From 2-chloroethyl chloroformate in a yield of _{HRMS: [C 20 H 21 ClN} 2 O 7 S + H] + calcd 469.08308 for; found ^{(ESI-FTMS, [M +} H] 1+) 469.0835.

Example 30: Preparation of (S) -2- (8-((2-bromoethoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid described in Example 28 Following a procedure similar to that using 2-bromoethyl chloroformate and using (S) -2- (8-((2-bromoethoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamide ) -3-Methylbutanoic acid was prepared as a white solid in 90% yield. MS (ES-) 513.02.

Example 31: Preparation of (S) -2- (8- (isopropoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Analogous to the procedure described in Example 28 According to the procedure, 100% of (S) -2- (8- (isopropoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid as a white solid using isopropyl chloroformate The yield was prepared. _{HRMS: [C 21 H 24 N} 2 O 7 S + H] + calcd 449.13770 for; found ^{(ESI-FTMS, [M +} H] 1+) 449.1379.

Example 32: Preparation of (S) -2- (8-((4-fluorophenoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid described in Example 28 Following a procedure similar to that using 4-fluorophenyl chloroformate and using (S) -2- (8-((4-fluorophenoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamide ) -3-Methylbutanoic acid was prepared as a white solid in 90% yield. _{HRMS: [C 24 H 21 FN} 2 O 7 S + H] + calcd 501.11263 for; found ^{(ESI-FTMS, [M +} H] 1+) 501.1125.

Example 33: Preparation of (S) -2- (8-((2-chlorophenoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid described in Example 28. (S) -2- (8-((2-chlorophenoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamide) using 2-chlorophenyl chloroformate following a procedure similar to that -3-Methylbutanoic acid was prepared as a white solid in 96% yield. _{HRMS: [C 24 H 21 ClN} 2 O 7 S + NH 4] + calcd 534.10963 for; found ^{(ESI-FTMS, [M +} NH4] 1+) 534.1096.

Example 34: Preparation of (S) -2- (8-((but-2-ynyloxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid As described in Example 28. According to a procedure similar to that described above, but-2-ynylchloroformate was used and (S) -2- (8-((but-2-ynyloxy) carbonylamino) dibenzo [b, d] furan- 3-sulfonamido) -3-methylbutanoic acid was prepared as a white solid in 100% yield. _HRMS: calcd 459.12205 for _{[C 22 H 22 N 2 O} 7 S + H]; Found ^{(ESI-FTMS, [M +} H] 1+) 459.1216.

Example 35: Preparation of (S) -3-methyl-2- (8- (p-tolyloxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) butanoic acid Procedure described in Example 28 (S) -3-Methyl-2- (8- (p-tolyloxycarbonylamino) dibenzo [b, d] furan-3-sulfonamide using p-tolyl chloroformate according to a procedure similar to ) Butanoic acid was prepared as a white solid in 99% yield. _{HRMS: [C 25 H 24 N} 2 O 7 S + H] + calcd 497.13770 for; found ^{(ESI-FTMS, [M +} H] 1+) 497.1377.

Example 36: Preparation of (S) -3-methyl-2- (8- (phenoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) butanoic acid Analogous to the procedure described in Example 28 According to the procedure, 93% of (S) -3-methyl-2- (8- (phenoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) butanoic acid as a white solid using phenyl chloroformate The yield was prepared. _{HRMS: [C 24 H 22 N} 2 O 7 S + H] + calcd 483.12205 for; found ^{(ESI-FTMS, [M +} H] 1+) 483.1229.

Example 37: Preparation of (S) -2- (8- (benzyloxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Similar to the procedure described in Example 28 According to the procedure, 93% of (S) -2- (8- (benzyloxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid as a white solid using benzyl chloroformate The yield was prepared. _{HRMS: [C 25 H 24 N} 2 O 7 S + H] + calcd 497.13770 for; found ^{(ESI-FTMS, [M +} H] 1+) 497.1387.

Example 38: Preparation of (S) -2- (8- (hexyloxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Analogous to the procedure described in Example 28 97% of (S) -2- (8- (hexyloxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid as a white solid using hexyl chloroformate according to the procedure Prepared in a yield of _{HRMS: [C 24 H 30 N} 2 O 7 S + H] + calcd 491.18465 for; found ^{(ESI-FTMS, [M +} H] 1+) 491.1857.

Example 39: Preparation of (S) -2- (8-((2-fluoroethoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid described in Example 28. Following a procedure similar to that using 2-fluoroethyl chloroformate and using (S) -2- (8-((2-fluoroethoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamide ) -3-Methylbutanoic acid was prepared as a white solid in 100% yield. _{HRMS: [C 20 H 21 FN} 2 O 7 S + H] + calcd 453.11263 for; found ^{(ESI-FTMS, [M +} H] 1+) 453.1135.

Example 40: Preparation of (S) -2- (8- (methoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid A procedure similar to that described in Example 28 In accordance with the following, 95% yield of (S) -2- (8- (methoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid as a white solid was Prepared at a rate. MS (ES-) 419.10.

Example 41: Preparation of (S) -2- (8- (ethoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid A procedure similar to that described in Example 28 In accordance with the procedure of (S) -2- (8- (ethoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid as a white solid using 95% yield of ethyl chloroformate. Prepared at a rate. MS (ES-) 433.1.

Example 42 Preparation of (S) -3-Methyl-2- (8- (propoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) butanoic acid Analogous to the procedure described in Example 28 According to the procedure, 100% of (S) -3-methyl-2- (8- (propoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) butanoic acid as a white solid using propyl chloroformate Prepared in a yield of _{HRMS: [C 21 H 24 N} 2 O 7 S + H] + calcd 449.13770 for; found ^{(ESI-FTMS, [M +} H] 1+) 449.1386.

Example 43: Preparation of (S) -2- (8- (butoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid A procedure similar to that described in Example 28 In accordance with the procedure of (S) -2- (8- (butoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid as a white solid using 100% yield of butyl chloroformate. Prepared at a rate. _{HRMS: [C 22 H 26 N} 2 O 7 S + H] + calcd 463.15335 for; found ^{(ESI-FTMS, [M +} H] 1+) 463.1527.

Example 44: Preparation of (S) -2- (8-((but-3-ynyloxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid As described in Example 28. (S) -2- (8-((but-3-ynyloxy) carbonylamino) dibenzo [b, d] furan- 3-sulfonamido) -3-methylbutanoic acid was prepared as a white solid in 97% yield. _{HRMS: [C 22 H 22 N} 2 O 7 S + H] + calcd for, 459.12205; found ^{(ESI-FTMS, [M +} H] 1+) 459.1215.

Example 45: (S) -2- (8- (3- (3,5-dimethylisoxazol-4-yl) ureido) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Preparation Following a procedure similar to that described in Examples 5 and 28, using 3,5-dimethylisoxazol-4-yl isocyanate, (S) -2- (8- (3- (3,5 -Dimethylisoxazol-4-yl) ureido) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid was prepared as a white solid. _{HRMS: [C 23 H 24 N} 4 O 7 S + H] + calcd 501.14385 for; found ^{(ESI-FTMS, [M +} H] 1+) 501.1453.

Example 46: Preparation of (S) -3-methyl-2- (8- (3-thiophen-3-ylureido) dibenzo [b, d] furan-3-sulfonamido) butanoic acid described in Examples 5 and 28 (S) -3-Methyl-2- (8- (3-thiophen-3-ylureido) dibenzo [b, d] using 3-thiophen-3-yl isocyanate following a procedure similar to that described Furan-3-sulfonamido) butanoic acid was prepared as a white solid. _{HRMS: [C 22 H 21 N} 3 O 6 S 2 + H] + calcd 488.09445 for; found ^{(ESI-FTMS, [M +} H] 1+) 488.0948.

Example 47: Preparation of (S) -3-methyl-2- (8- (3- (3,4,5-trimethoxyphenyl) ureido) dibenzo [b, d] furan-3-sulfonamido) butanoic acid Following procedures similar to those described in Examples 5 and 28, using 3,4,5-trimethoxyphenyl isocyanate, (S) -3-methyl-2- (8- (3- (3 4,5-trimethoxyphenyl) ureido) dibenzo [b, d] furan-3-sulfonamido) butanoic acid was prepared as a white solid. _{HRMS: [C 27 H 29 N} 3 O 9 S + H] + calcd 572.16973 for; found ^{(ESI-FTMS, [M +} H] 1+) 572.17.

Example 48: Preparation of (S) -2- (8- (3- (3,4-difluorophenyl) ureido) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Example 5 and According to a procedure similar to that described in 28, using 3,4-difluorophenyl isocyanate, (S) -2- (8- (3- (3,4-difluorophenyl) ureido) dibenzo [b, d] Furan-3-sulfonamido) -3-methylbutanoic acid was prepared as a white solid. _{HRMS: [C 24 H 21 F} 2 N 3 O 6 S + H] + calcd 518.11919 for; found ^{(ESI-FTMS, [M +} H] 1+) 518.1196.

Example 49: Preparation of (S) -3-methyl-2- (8- (3- (3-phenoxyphenyl) ureido) dibenzo [b, d] furan-3-sulfonamido) butanoic acid Examples 5 and 28 (S) -3-methyl-2- (8- (3- (3-phenoxyphenyl) ureido) dibenzo [b, d] using a 3-phenoxyphenyl isocyanate and following a procedure similar to that described in ] Furan-3-sulfonamido) butanoic acid was prepared as a white solid. _{HRMS: [C 30 H 27 N} 3 O 7 S + H] + calcd 574.16425 for; found ^{(ESI-FTMS, [M +} H] 1+) 574.1652.

Example 50: Preparation of (S) -3-methyl-2- (8-ureidodibenzo [b, d] furan-3-sulfonamido) butanoic acid Similar to the procedure described in Examples 5, 13 and 28 According to the procedure, (S) -3-methyl-2- (8-ureidodibenzo [b, d] furan-3-sulfonamido) butanoic acid was prepared as a pale yellow solid. _{HRMS: [C 18 H 19 N} 3 O 6 S + H] + calcd 406.10673 for; found ^{(ESI-FTMS, [M +} H] 1+) 406.1079.

Example 51: Preparation of (S) -2- (8- (3- (2,6-dichloropyridin-4-yl) ureido) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Following procedures similar to those described in Examples 5 and 28, using 2,6-dichloropyridin-4-yl isocyanate, (S) -2- (8- (3- (2,6-dichloro) Pyridin-4-yl) ureido) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid was prepared as a white solid. _{HRMS: [C 23 H 20 Cl} 2 N 4 O 6 S + H] + calcd 551.05534 for; found ^{(ESI-FTMS, [M +} H] 1+) 551.0572.

Example 52: Preparation of (S) -2- (8- (3- (4- (dimethylamino) phenyl) ureido) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid And (S) -2- (8- (3- (4- (dimethylamino) phenyl) ureido) dibenzo using 4- (dimethylamino) phenyl isocyanate and following a procedure similar to that described in [B, d] furan-3-sulfonamido) -3-methylbutanoic acid was prepared as a white solid. _{HRMS: [C 26 H 28 N} 4 O 6 S + H} + calcd 525.18023 for; found ^{(ESI-FTMS, [M +} H] 1+) 525.1815.

Example 53: (S) -3-Methyl-2- (8- (3- (2- (thiophen-2-yl) ethyl) ureido) dibenzo [b, d] furan-3-sulfonamido) butanoic acid Preparation Following a procedure similar to that described in Examples 5 and 28, using 2- (thiophen-2-yl) ethyl isocyanate, (S) -3-methyl-2- (8- (3- ( 2- (Thiophen-2-yl) ethyl) ureido) dibenzo [b, d] furan-3-sulfonamido) butanoic acid was prepared as a white solid. _{HRMS: [C 24 H 25 N} 3 O 6 S 2 + H] + calcd 516.12575 for; found ^{(ESI-FTMS, [M +} H] 1+) 516.1247.

Example 54: Preparation of (S) -3-methyl-2- (8- (3- (4- (trifluoromethoxy) phenyl) ureido) dibenzo [b, d] furan-3-sulfonamido) butanoic acid Following procedures similar to those described in Examples 5 and 28, using 4- (trifluoromethoxy) phenyl isocyanate, (S) -3-methyl-2- (8- (3- (4- (tri Fluoromethoxy) phenyl) ureido) dibenzo [b, d] furan-3-sulfonamido) butanoic acid was prepared as a white solid. _{HRMS: [C 25 H 22 F} 3 N 3 O 7 S + H] + calcd 566.12033 for; found ^{(ESI-FTMS, [M +} H] 1+) 566.1217.

Example 55: Preparation of (S) -2- (8- (3-cyclopentylureido) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid The procedure described in Examples 5 and 28 was followed. Follow a similar procedure to prepare (S) -2- (8- (3-cyclopentylureido) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid as a white solid using cyclopentyl isocyanate did. _{HRMS: [C 23 H 27 N} 3 O 6 S + H] + calcd 474.16933 for; found ^{(ESI-FTMS, [M +} H] 1+) 474.1696.

Example 56: Preparation of (S) -2- (8- (3- (4-fluorobenzyl) ureido) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid In Examples 5 and 28 Following procedures similar to those described, using 4-fluorobenzyl isocyanate, (S) -2- (8- (3- (4-fluorobenzyl) ureido) dibenzo [b, d] furan-3- Sulfonamido) -3-methylbutanoic acid was prepared as a white solid. _{HRMS: [C 25 H 24 FN} 3 O 6 S + H] + calcd 514.14426 for; found ^{(ESI-FTMS, [M +} H] 1+) 514.1445.

Example 57: Preparation of (S) -3-methyl-2- (8- (methylsulfonamido) -dibenzo [b, d] furan-3-sulfonamido) butanoic acid Procedure described in Examples 18 and 28 The (S) -3-methyl-2- (8- (methylsulfonamido) -dibenzo [b, d] furan-3-sulfonamido) butanoic acid was converted to white using methylsulfonyl chloride according to a procedure similar to Prepared as a solid. _{HRMS: [C 18 H 20 N} 2 O 7 S 2 + H] + calcd 441.07847 for; found ^{(ESI-FTMS, [M +} H] 1+) 441.0784.

Example 58: Preparation of (S) -2- [8- (methoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido] -3-methylbutanoic acid Step 1: Dibenzo [b, d] thiophene-3 Preparation of sulfonyl chloride 5- (Trifluoromethyl) -5H-dibenzo [b, d] thiophenium-3-sulfonate (200 mg) was mixed with 10 mL thionyl chloride and a few drops of dry DMF. The mixture was stirred at 80 ° C. for 24 hours. Excess SOCl ₂ was removed under reduced pressure and the residue was triturated with ice cold water and then filtered. 150 mg of dibenzo [b, d] thiophene-3-sulfonyl chloride was obtained as a white solid.

Step 2: Preparation of 8-nitrodibenzo [b, d] thiophene-3-sulfonyl chloride Dibenzo [b, d] thiophene-3-sulfonyl chloride (2.0 g, 7.1 mmol) is mixed with trifluoroacetic acid and the mixture Was stirred at room temperature. Nitric acid (> 90%, fuming, 0.29 mL) was added dropwise. The mixture was stirred at room temperature for 3 hours and filtered. The solid was washed with TFA and air dried. 8-Nitrodibenzo [b, d] thiophene-3-sulfonyl chloride (1.1 g) was obtained as an off-white solid.

Step 3: Preparation of (S) -tert-butyl 3-methyl-2- (8-nitrodibenzo [b, d] thiophene-3-sulfonamido) butanoate 8-nitrodibenzo [b, d] thiophene-3-sulfonyl Chloride (450 mg, 1.38 mmol) and tert-butyl 2-amino-3-methylbutanoate hydrochloride (316 mg, 1.51 mmol) in 3 mL of CH ₂ Cl ₂ and N, N-diisopropylethylamine (392 mg, 3. 0 mmol.). The mixture was stirred at room temperature for 4 hours and purified by silica gel column chromatography to yield 450 mg (S) -tert-butyl 3-methyl-2- (8-nitrodibenzo [b, d] thiophene-3-sulfonamide). Butanoate was obtained as an off-white solid.

Step 4: Preparation of (S) -tert-butyl 2- (8-aminodibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate (S) -tert-butyl 3-methyl-2 -(8-Nitrodibenzo [b, d] thiophene-3-sulfonamido) butanoate (450 mg) was mixed with 20 mL MeOH and 100 mg Pd / C. The reaction was performed in a Parr shaker at room temperature overnight under 50 psi H ₂ . The reaction mixture was filtered through celite and the filtrate was concentrated to give 370 mg of (S) -tert-butyl 2- (8-aminodibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate. Was obtained as an off-white solid.

Step 5. Preparation of (S) -tert-butyl 2- (8- (methoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate (S) -tert-butyl 2- (8 - amino dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate (109 mg, 0.25 mmol) and DMAP (37 mg, 0.3 mmol) was dissolved in _CH 2 _Cl 2 (3mL), Methyl chloroformate (28 mg, 0.28 mmol) was added. The mixture was stirred overnight at room temperature and purified by silica gel column chromatography to give 115 mg (S) -tert-butyl 2- (8- (methoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamide) -3-Methylbutanoate was obtained as a white solid.

Step 6. Preparation of (S) -2- (8- (methoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid (S) -tert-butyl 2- (8- (methoxycarbonylamino) ) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate (115 _mg), was dissolved in a mixture of CH ₂ Cl 2 and (2 mL) and TFA (2 mL). The solution was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was triturated in CH ₃ CN / water followed by a lyophilization process. 95 mg of (S) -2- (8- (methoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was obtained as a white solid. _{HRMS: [C 19 H 20 N} 2 O 6 S 2 + H] + calcd 437.08355 for; found ^{(ESI-FTMS, [M +} H] 1+) 437.0833.

  The sodium salt was prepared by treating (S) -2- [8- (methoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido] -3-methylbutanoic acid with 1.0 equivalent of NaOH. The salt was obtained as a white solid.

Example 59: Preparation of (R) -2- (8- (methoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid A procedure similar to that described in Example 58 (R) -tert-butyl 2- (8-aminodibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate and methyl chloroformate using (8- (Methoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was obtained as a white solid. _{HRMS: [C 19 H 20 N} 2 O 6 S 2 + H] + calcd 437.08355 for; found ^{(ESI-FTMS, [M +} H] 1+) 437.0822.

Example 60: Preparation of (S) -3-methyl-2- (8- (methylsulfonamido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid The procedure described in Examples 18 and 58 was followed. According to a similar procedure, using (S) -3-methyl-2- (8- (methylsulfonamido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid as a white solid using methylsulfonyl chloride Obtained. _{HRMS: [C 18 H 20 N} 2 O 6 S 3 + H] + calcd 457.05562 for; found ^{(ESI-FTMS, [M +} H] 1+) 457.0546.

Example 61 Preparation of (R) -3-methyl-2- (8- (methylsulfonamido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid The procedure described in Examples 18 and 58 was followed. Following a similar procedure, using (R) -tert-butyl 2- (8-aminodibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate methylsulfonyl chloride, 3-Methyl-2- (8- (methylsulfonamido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid was obtained as a white solid. _{HRMS: [C 18 H 20 N} 2 O 6 S 3 + H] + calcd 457.05562 for; found ^{(ESI-FTMS, [M +} H] 1+) 457.0546.

Example 62: Preparation of (R) -2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid (R) -tert-butyl 2- obtained from Example 1 (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate was dissolved in 4 mL of TFA / CH ₂ Cl ₂ (1: 1). The solution was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue was triturated in ether / hexane and then filtered to give (R) -2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3- Methylbutanoic acid was obtained as a beige solid in 94% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.81 (dd, J = 13.64, 6.82 Hz, 6H), 1.87-1.98 (m, 1H), 3.56 (dd , J = 9.47, 5.94 Hz, 1H), 6.71 (dd, J = 8.46, 1.89 Hz, 1H), 6.81 (d, J = 1.77 Hz, 1H), 7. 64-7.68 (m, 1H), 7.68-7.73 (m, 1H), 7.84 (d, J = 8.34 Hz, 1H), 7.94 (d, J = 9.35 Hz) , 1H), 8.26 (dd, J = 2.02, 0.51 Hz, 1H) and 12.50 (s, 1H); MS (ES−): 361.07.

  The sodium salt was prepared by treating (R) -2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid with 1.0 equivalent of NaOH. The salt was obtained as a white solid.

Example 63: Preparation of (S) -2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid A procedure similar to that described in Example 62 was followed (S ) -Tert-butyl 2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate and (S) -2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid was obtained as a beige solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.81 (dd, J = 13.64, 6.82 Hz, 6H), 1.86-1.99 (m, 1H), 3.56 (dd , J = 9.47, 5.94 Hz, 1H), 5.83 (s, 2H), 6.69 (dd, J = 8.46, 1.89 Hz, 1H), 6.80 (d, J = 1.77 Hz, 1H), 7.61-7.67 (m, 1H), 7.68-7.74 (m, 1H), 7.83 (d, J = 8.34 Hz, 1H), 7. 94 (d, J = 9.35 Hz, 1H), 8.25 (d, J = 1.77 Hz, 1H) and 12.49 (s, 1H); MS (ES−) 361.05.

Example 64: Preparation of (S) -2- (8-aminodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid A procedure similar to that described in Example 62 was followed (S ) -Tert-butyl 2- (8-aminodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate starting from (S) -2- (8-aminodibenzo [b, d] Furan-3-sulfonamido) -3-methylbutanoic acid was prepared as a beige solid. _{HRMS: [C 17 H 18 N} 2 O 5 S + H] + calcd 363.10092 for; found ^{(ESI-FTMS, [M +} H] 1+) 363.1009.

Example 65: Preparation of (S) -2- (7- (3-cyclopentylureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid Step 1: 7-nitro-5- (tri Preparation of fluoromethyl) -5H-dibenzo [b, d] thiophenium-3-sulfonate 5- (trifluoromethyl) -5H-dibenzo [b, d] thiophenium-3-sulfonate (5.0 g) was fuming 30%. It was added in portions to a mixture of sulfuric acid (3.3 mL) and _90% HNO 3 _(1.7mL). The mixture was stirred at room temperature overnight and then added dropwise into cold diethyl ether (250 mL). 7-nitro-5- (trifluoromethyl) -5H-dibenzo [b, d] thiophenium-3-sulfonate precipitated and was collected by filtration and dried under reduced pressure (5.37 g, 95% yield). ).

Step 2: Preparation of 7-nitrodibenzo [b, d] thiophene-3-sulfonyl chloride 7-nitro-5- (trifluoromethyl) -5H-dibenzo [b, d] thiophenium-3-sulfonate (5 g) ₂ (35 mL) and a few drops of DMF were added. The mixture was heated to 80 ° C. for 24 hours. Excess SOCl ₂ is removed under reduced pressure and the residue is triturated twice with CH ₂ Cl ₂ to give a quantitative yield of 7-nitrodibenzo [b for use in the next step without further purification. , D] thiophene-3-sulfonyl chloride was obtained.

Step 3: Preparation of (S) -tert-butyl 3-methyl-2- (7-nitrodibenzo [b, d] thiophene-3-sulfonamido) butanoate Similar to the procedure described in Step 4 of Example 1 According to the procedure, (S) -tert-butyl 3-methyl-2- (7-nitrodibenzo [b, d] thiophene-3-sulfonamido) butanoate was obtained as a white solid in 95% yield. ¹ H NMR (DMSO-d ₆ ) δ ppm 0.89 (d, J = 6.6 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H), 1.15 (s, 9H), 2.00 (m, 1H), 3.63 (d, J = 6.3 Hz, 1H), 7.81 (sbr, 1H), 7.98 (dd, J = 8.5, 1.9 Hz, 1H), 8.35 (dd, J = 8.5, 1.9 Hz, 1H), '8.56 (dd, J = 1.6, 0.6 Hz, 1H), 8.66 (d, J = 8.2 Hz, 1H), 8.67 (d, J = 8.5 Hz, 1H) and 9.05 (d, J = 2.2 Hz, 1H).

Step 4: Preparation of (S) -tert-butyl 2- (7-aminodibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate (S) -tert-butyl 3-methyl-2 -(7-nitrodibenzo [b, d] thiophene-3-sulfonamido) butanoate was dissolved in MeOH and the resulting mixture was stirred overnight in the presence of 10% Pd / C (10% w / w) Treated with hydrogen (40 psi). After removing the catalyst by filtration and evaporating the solvent, (S) -tert-butyl 2- (7-aminodibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate was quantitatively analyzed. Obtained in yield. ¹ H NMR (DMSO-d ₆ ) δ ppm 0.82 (d, J = 6.6 Hz, 3H), 0.85 (d, J = 6.6 Hz, 3H), 1.07 (s, 9H), 1.92 (m, 1H), 3.50 (dd, J = 9.7, 6.3 Hz, 1H), 5.71 (sbr, 2H), 6.79 (dd, J = 8.5) 1.9 Hz, 1H), 7.05 (d, J = 1.9 Hz, 1H), 7.72 (dd, J = 8.5, 1.9 Hz, 1H), 8.01 (d, J = 9 .1 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H) and 8.21 (d, J = 1.9 Hz, 1H) .

Steps 5 and 6: Preparation of (S) -2- (7- (3-cyclopentylureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid (S) -tert-butyl 2- ( 7-aminodibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate (250 mg, 0.57 mmol) was dissolved in 5 mL of dry CH ₂ Cl ₂ and cyclopentyl isocyanate (1.2 eq) And the mixture was stirred at room temperature for 24 hours. The crude product was purified using a silica gel cartridge. The product was treated with 30% TFA in CH ₂ Cl ₂ for 6 hours and purified by preparative high performance liquid chromatography (HPLC) to give (S) -2- [7- (3-cyclopentyl-ureido) -dibenzo Thiophen-3-sulfonylamino] -3-methyl-butyric acid was obtained. ( ¹ H CDCl ₃ ) δ ppm 0.84 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.9 Hz, 3H), 1.49-1.32 (m, 2H) 1.74-1.53 (m, 4H), 2.14-1.88 (m, 3H), 3.71 (m, 1H), 4.10 (dt, J = 13.2, 6.. 6 Hz, 1H), 5.33 (d, J = 10.1 Hz, 1H), 7.29 (dd, J = 8.8, 2.2 Hz, 1H), 7.83 (dd, J = 8.2) , 1.6 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 2.2 Hz, 1H) and 8.24 (d, J = 1.6 Hz, 1H); MS (ES +) 490.1.

  The sodium salt was prepared by treating (S) -2- [7- (3-cyclopentyl-ureido) -dibenzothiophene-3-sulfonylamino] -3-methyl-butyric acid with 1.0 equivalent of NaOH. The salt was obtained as a white solid.

Example 66: (S) -3-Methyl-2- (7- (3- (2- (thiophen-2-yl) ethyl) ureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid Preparation Following a procedure analogous to that described in Example 65, using 2- (thiophen-2-yl) ethyl isocyanate, (S) -3-methyl-2- (7- (3- (2- (Thiophen-2-yl) ethyl) ureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid was prepared. ( ¹ H DMSO 353K) δ ppm 0.86 (d, J = 6.9 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H), 1.99 (m, 1H), 3.04 (T, J = 6.6 Hz, 2H), 3.45 (dt, J = 6.6, 6.0 Hz, 2H), 3.63 (d, J = 6.0 Hz, 1H), 6.22 ( t, J = 6.0 Hz, 1H), 6.93 (m, 1H), 6.98 (dd, J = 5.0, 3.5 Hz, 1H), 7.31 (dd, J = 5.0 , 1.3 Hz, 1H), 7.47 (dd, J = 8.8, 1.9 Hz, 1H), 7.84 (dd, J = 8.5, 1.9 Hz, 1H), 8.19 ( d, J = 2.2 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.30 (d, J = 8.5 Hz, 1H), 8.34 (d, J = 1) .6Hz, 1H) and .67 (s br, 1H); MS (ES +) 532.1.

Example 67: Preparation of (S) -2- (7- (3- (4-fluorophenyl) ureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid As described in Example 65. (S) -2- (7- (3- (4-Fluorophenyl) ureido) dibenzo [b, d] thiophene-3-sulfonamide using a procedure similar to that described above and using 4-fluorophenyl isocyanate ) -3-Methylbutanoic acid was prepared. ¹ H NMR (DMSO-d ₆ ) δ ppm 0.80 (d, J = 6.9 Hz, 3H), 0.84 (d, J = 6.6 Hz, 3H), 1.95 (m, 1H), 3.60 (dd, J = 9.4, 6.0 Hz, 1H), 7.14 (dd, J = 8.8, 8.8 Hz, 2H), 7.56-7.45 (m, 3H) 7.83 (dd, J = 8.5, 1.6 Hz, 1H), 8.01 (d br, J = 9.4 Hz, 1H), 8.27 (d, J = 1.9 Hz, 1H) , 8.33 (d, J = 8.5 Hz, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.86 ( sbr, 1H), 9.07 (s, 1H) and 12.48 (sbr, 1H); MS (ES +) 516.1.

Example 68: Preparation of (S) -3-methyl-2- (7- (3-phenethylureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid Analogous to the procedure described in Example 65 (S) -3-methyl-2- (7- (3-phenethylureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid was prepared using 3-phenethyl isocyanate according to the procedure described above. . ¹ H NMR (CDCl ₃ ) δ ppm 0.84 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.9 Hz, 3H), 2.06 (m, 1H), 2. 85 (t, J = 6.9 Hz, 2H), 3.5 (t, J = 6.9 Hz, 2H), 3.72 (m, 1H), 5.32 (d, J = 9.7 Hz, 1H) ), 7.33-7.14 (m, 6H), 7.83 (dd, J = 8.5, 1.9 Hz, 1H), 7.96 (d, J = 8.5 Hz, 1H), 8 .04 (d, J = 8.2 Hz, 1H), 8.19 (d, J = 1.9 Hz, 1H) and 8.25 (d, J = 1.6 Hz, 1H); MS (ES +) 526. 1.

Example 69 Preparation of (S) -2- (7- (3-Benzylureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid Analogous to the procedure described in Example 65 According to the procedure, (S) -2- (7- (3-benzylureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was prepared using 3-benzyl isocyanate. ¹ H NMR (DMSO-d ₆ ) δ ppm 0.80 (d, J = 6.9 Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H), 1.95 (m, 1H), 3.59 (m, 1H), 4.34 (d, J = 5.6 Hz, 2H), 6.79 (7 br, J = 5.7 Hz, 1H), 7.22-7.37 (m, 5H), 7.46 (dd, J = 8.7 2.0 Hz, 1H), 7.81 (dd, J = 8.5 2.1 Hz, 1H), 8.0 (dbr, J = 9. 5 Hz, 1H), 8.25 (d, J = 1.8 Hz 1H), 8.27 (d, J = 8.2 Hz, 1H), 8.34 (d, J = 8.1 Hz, 1H), 8 .35 (s, 1H), 8.96 (s, 1H) and 12.49 (sbr, 1H); MS (ES +) 512.1.

Example 70: Preparation of (S) -2- (7- (3- (4-fluorobenzyl) ureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid As described in Example 65. (S) -2- (7- (3- (4-fluorobenzyl) ureido) dibenzo [b, d] thiophene-3-sulfonamide using a procedure similar to that described above, using 4-fluorobenzyl isocyanate. ) -3-Methylbutanoic acid was prepared. ¹ H NMR (DMSO-d ₆ ) δ ppm 0.80 (d, J = 6.9 Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H), 1.95 (m, 1H), 3.53 (m, 1H), 4.31 (d, J = 5.9 Hz, 2H), 6.84 (m, 1H), 7.16 (dd, J = 9.1 9.1 Hz, 2H) 7.37 (dd, J = 9.1 6.5 Hz, 2H), 7.45 (d br, J = 9.1 Hz, 1H), 7.80 (dd, J = 8.9 2.0 Hz, 1H), 7.95 (sbr, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 9.2 Hz, 1H), 8.34 (d, J = 8.3 Hz, 1H), 8.35 (sbr, 1H), 9.00 (sbr, 1H) and 12.51 (sbr, 1H); MS (ES +) 530.1.

Example 71 Preparation of (S) -3-Methyl-2- (7- (3-p-tolylureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid Procedure described in Example 65 (S) -3-Methyl-2- (7- (3-p-tolylureido) dibenzo [b, d] thiophene-3-sulfonamide using 3-p-tolyl isocyanate following the procedure similar to ) Butanoic acid was prepared. ¹ H NMR (DMSO-d ₆ ) δ ppm 0.81 (d, J = 6.9 Hz, 3H), 0.85 (d, J = 6.9 Hz, 3H), 1.95 (m, 1H), 2.27 (s, 3H), 3.61 (dd, J = 9.5 6.1 Hz, 1H), 7.11 (d, J = 8.9 Hz, 2H), 7.38 (d, J = 8.9 Hz, 2H), 7.53 (dd, J = 8.3 1.9 Hz, 1H), 7.83 (dd, J = 8.6 1.6 Hz, 1H), 8.05 (d, J = 9.6 Hz, 1 H), 8.28 (d, J = 1.9 Hz, 1 H), 8.33 (d, J = 8.4 Hz, 1 H), 8.38 (d, J = 8.2 Hz, 1H), 8.39 (d, J = 1.9 Hz, 1H), 8.69 (sbr, 1H), 9.00 (sbr, 1H) and 12.51 (sbr, 1H); MS ( ES +) 12.2.

Example 72: Preparation of (S) -3-methyl-2- (7- (3- (3,4,5-trimethoxyphenyl) ureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid Following a procedure similar to that described in Example 65 and using 3,4,5-trimethoxyphenyl isocyanate, (S) -3-methyl-2- (7- (3- (3,4, 5-Trimethoxyphenyl) ureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid was prepared. ¹ H NMR (DMSO-d ₆ ) δ ppm 0.81 (d, J = 6.9 Hz, 3H), 0.85 (d, J = 6.9 Hz, 3H), 1.95 (m, 1H), 3.61 (dd, J = 9.1 6.0 Hz, 1H), 3.63 (s, 3H), 3.78 (s, 6H), 6.84 (s, 2H), 7.52 (dd , J = 8.1 1.5 Hz, 1H), 7.84 (dd, J = 8.6 1.5 Hz, 1H), 8.05 (d, J = 9.6 Hz, 1H), 8.41−. 8.30 (m, 4H), 8.75 (s br, 1H), 8.99 (s br, 1H) and 12.51 (s br, 1H); MS (ES +) 588.2.

Example 73: Preparation of (S) -2- (7- (3-ethylureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid Similar to the procedure described in Example 65 According to the procedure, (S) -2- (7- (3-ethylureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was prepared using ethyl isocyanate. ¹ H NMR (DMSO-d ₆ ) δ ppm 0.81 (d, J = 6.9 Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H), 1.09 (t, J = 5 .6 Hz, 3H), 1.95 (m, 1H), 3.15 (dq, J = 7.0, 5.6 Hz, 2H), 3.58 (m, 1H), 6.27 (t br, J = 5.5 Hz, 1 H), 7.45 (dd, J = 8.6 2.0 Hz, 1 H), 7.81 (dd, J = 8.5 1.8 Hz, 1 H), 8.00 (d br , J = 9.0 Hz, 1H), 8.23 (d, J = 1.8 Hz, 1H), 8.26 (d, J = 8.3 Hz, 1H), 8.34 (d, J = 8. 3 Hz, 1 H), 8.36 (d, J = 1.8 Hz, 1 H), 8.82 (s br, 1 H) and 12.51 (s br, 1 H); MS (ES +) 450.1.

Example 74: Preparation of (S) -2- (7- (3- (3,4-difluorophenyl) ureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid Following procedures similar to those described, (S) -2- (7- (3- (3,4-difluorophenyl) ureido) dibenzo [b, d] using 3,4-difluorophenyl isocyanate. Thiophene-3-sulfonamido) -3-methylbutanoic acid was prepared. ¹ H NMR (DMSO-d ₆ ) δ ppm 0.81 (d, J = 6.9 Hz, 3H), 0.85 (d, J = 6.9 Hz, 3H), 1.96 (m, 1H), 3.6 (dd, J = 9.4 6.3 Hz, 1H), 7.17 (m, 1H), 7.37 (dt, J = 10.1 9.2 Hz, 1H), 7.54 (d br, J = 8.3 Hz, 1H), 7.70 (ddd, J = 13.8 7.4 Hz, 1H), 7.84 (dd, J = 8.7 1.4 Hz, 1H), 8.04 (sbr, 1H), 8.27 (sbr, 1H), 8.41-8.31 (m, 3H), 9.04 (sbr, 1H), 9.15 (sbr, 1H) and 12.51 (sbr, 1H); MS (ES +) 534.1.

Example 75: Preparation of (S) -3-methyl-2- (7- (3- (4- (trifluoromethyl) phenyl) ureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid Following a procedure similar to that described in Example 65 and using 4- (trifluoromethyl) phenyl isocyanate, (S) -3-methyl-2- (7- (3- (4- (trifluoromethyl ) Phenyl) ureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid was prepared. ¹ H NMR (DMSO-d ₆ ) δ ppm 0.81 (d, J = 6.9 Hz, 3H), 0.85 (d, J = 6.9 Hz, 3H), 1.96 (m, 1H), 3.61 (dd, J = 9.7 6.1 Hz, 1H), 7.57 (dd, J = 8.8 1.9 Hz, 1H), 7.66 (d, J = 9.2 Hz, 2H) 7.71 (d, J = 9.2 Hz, 2H), 7.84 (dd, J = 8.4 1.5 Hz, 1H), 8.05 (d br, J = 9.2 Hz, 1H), 8.29 (d, J = 1.8 Hz, 1H), 1.36 (d, J = 8.5 Hz, 1H), 8.40 (d, J = 8.0 Hz, 1H), 8.40 (d , J = 1.8 Hz, 1H), 9.20 (sbr, 1H), 9.25 (sbr, 1H) and 12.51 (sbr, 1H); MS (ES +) 566.1.

Example 76: (S) -2- (7- (3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ureido) dibenzo [b, d] thiophene-3-sulfone Preparation of Amido) -3-methylbutanoic acid Following a procedure similar to that described in Example 65, using 2,3-dihydrobenzo [b] [1,4] dioxin-6-yl isocyanate, (S ) -2- (7- (3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutane The acid was prepared. ¹ H NMR (DMSO-d ₆ ) δ ppm 0.81 (d, J = 6.9 Hz, 3H), 0.85 (d, J = 6.9 Hz, 3H), 1.96 (m, 1H), 3.61 (dd, J = 9.5, 5.9 Hz, 1H), 4.26-4.17 (m, 4H), 6.78 (d, J = 8.6 Hz, 1H), 6.84 ( dd, J = 8.6 2.3 Hz, 1H), 7.12 (d, J = 2.3 Hz, 1H), 7.51 (dd, J = 8.8 2.0 Hz, 1H), 7.83 (Dd, J = 8.4 1.6 Hz, 1H), 8.04 (d br, J = 9.7 Hz, 1H), 8.27 (d, J = 1.8 Hz, 1H), 8.32 ( d, J = 8.6 Hz, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.61 (sbr, 1H) , 8.96 (s r, IH) and 12.50 (s br, 1H); MS (ES +) 556.1.

Example 77 Preparation of (S) -3-Methyl-2- (7- (3-phenylureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid Analogous to the procedure described in Example 65 According to the prepared procedure, (S) -3-methyl-2- (7- (3-phenylureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid was prepared using phenyl isocyanate. ¹ H NMR (DMSO-d ₆ ) δ ppm 0.81 (d, J = 6.9 Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H), 1.96 (m, 1H), 3.60 (dd, J = 9.6 6.4 Hz, 1H), 7.00 (dd, J = 8.0 8.0 Hz, 1H), 7.31 (dd, J = 8.0 8.0 Hz) , 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.54 (m, 1H), 7.83 (dd, J = 8.5 1.6 Hz, 1H), 8.01 ( d br, J = 8.5 Hz, 1H), 8.28 (d, J = 1.8 Hz, 1H), 8.33 (d, J = 8.7 Hz, 1H), 8.38 (d, J = 5.3 Hz, 1H), 8.39 (d, J = 1.2 Hz, 1H), 8.82 (sbr, 1H), 9.07 (sbr, 1H) and 12.50 (sbr, 1H) ; M S (ES +) 498.1.

Example 78: Preparation of (S) -2- (7- (3- (4- (dimethylamino) phenyl) ureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid According to a procedure similar to that described in Example 1, using 4- (dimethylamino) phenyl isocyanate, (S) -2- (7- (3- (4- (dimethylamino) phenyl) ureido) dibenzo [b , D] thiophene-3-sulfonamido) -3-methylbutanoic acid was prepared. ¹ H NMR (DMSO-d ₆ ) δ ppm 0.81 (d, J = 6.9 Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H), 1.96 (m, 1H), 2.96 (s, 6H), 3.61 (dd, J = 9.7 5.7 Hz, 1H), 6.97 (s br, 2H), 7.40 (d br, J = 8.4 Hz, 2H), 7:53 (dd, J = 8.9 1.9 Hz, 1H), 7.83 (dd, J = 8.3 1.7 Hz, 1H), 8.05 (d, J = 10.0 Hz) , 1H), 8.28 (d, J = 1.8 Hz, 1H), 8.33 (d, J = 8.7 Hz, 1H), 8.37 (d, J = 5.1 Hz, 1H), 8 .39 (d, J = 1.3 Hz, 1H), 8.66 (sbr, 1H), 9.01 (sbr, 1H) and 12.54 (sbr, 1H); MS (ES +) 541 .2.

Example 79: Preparation of (S) -3-methyl-2- (7- (3-pyridin-4-ylureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid described in Example 65 Following a procedure similar to that using (S) -3-methyl-2- (7- (3-pyridin-4-ylureido) dibenzo [b, d] thiophene-3- Sulfonamido) butanoic acid was prepared. ¹ H NMR (DMSO-d ₆ ) δ ppm 0.81 (d, J = 6.9 Hz, 3H), 0.85 (d, J = 6.9 Hz, 3H), 1.96 (m, 1H), 3.63 (dd, J = 9.5 6.1 Hz, 1H), 7.63 (dd, J = 8.7 2.0 Hz, 1H), 7.86 (dd, J = 8.5 1.7 Hz) , 1H), 7.98 (d, J = 7.5 Hz, 2H), 8.08 (d, J = 9.4 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H), 8 .43 (m, 3H), 8.64 (d. J = 7.5 Hz, 2H), 10.14 (s br, 1H), 10.90 (s br, 1H) and 12.52 (s br, 1H); MS (ES +) 499.0.

Example 80: (S) -2- (7- (3- (3,5-dimethylisoxazol-4-yl) ureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid Preparation Following a procedure analogous to that described in Example 65, using 3,5-dimethylisoxazol-4-yl isocyanate, (S) -2- (7- (3- (3,5-dimethyl) Isoxazol-4-yl) ureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was prepared. ( ¹ H-DMSO 353 K) δ ppm 0.86 (d, J = 6.9 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H), 2.00 (m, 1H), 2. 17 (s, 3H), 2.33 (s, 3H), 3.61 (d, J = 5.7 Hz, 1H), 3.68 (sbr, 1H), 7.52 (dd, J = 8) .8 1.9 Hz, 1 H), 7.86 (dd, J = 8.3 1.6 Hz, 1 H), 7.90 (s br, 1 H), 8.20 (d, J = 1.7 Hz, 1 H) ), 8.25 (d, J = 8.6 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 1.5 Hz, 1H) and 9.07. (Sbr, 1H); MS (ES +) 517.0.

Example 81 Preparation of (S) -2- (7- (methoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid Analogous to the procedure described in Examples 1 and 65 According to the procedure described above, (S) -2- (7- (methoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was prepared using methyl chloroformate. ¹ H NMR (DMSO-d ₆ ) δ ppm 0.80 (d, J = 6.9 Hz, 3H), 0.83 (d, J = 6.6 Hz, 3H), 1.95 (m, 1H), 3.61 (m, 1H), 3.72 (s, 3H), 7.81 (d, J = 8.8 Hz, 1H), 7.91 (dd, J = 8.5, 1.6 Hz, 1H) ), 8.10 (m, 1H), 8.42 (d, J = 8.8 Hz, 1H), 8.50 (d, J = 8.5 Hz, 1H), 8.52 (d, J = 1) .3 Hz, 1H), 9.46 (s, 1H) and 12.45 (sbr, 1H); MS (ES +) 437.1.

Example 82: Preparation of (S) -2- (7- (ethoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid Similar to the procedure described in Examples 1 and 65 (S) -2- (7- (ethoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was prepared using ethyl chloroformate according to the procedure described above. ¹ H NMR (DMSO-d ₆ ) δ ppm 0.80 (d, J = 6.6 Hz, 3H), 0.83 (d, J = 6.6 Hz, 3H), 1.28 (t, J = 7 .2 Hz, 3H), 1.95 (m, 1H), 3.56 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H), 7.58 (dd, J = 8.8) , 1.9 Hz, 1H), 7.83 (dd, J = 8.8, 1.6 Hz, 1H), 7.99 (sbr, 1H), 8.22 (d, J = 1.9 Hz, 1H) ), 8.34 (d, J = 8.8, Hz, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.38 (d, J = 2.2 Hz, 1H), 10 .00 (s, 1 H) and 12.49 (s br, 1 H); MS (ES +) 450.9.

Example 83: Preparation of (S) -2- (7- (isobutoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid The procedure described in Examples 1 and 65 was followed. According to a similar procedure, (S) -2- (7- (isobutoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was prepared using isobutyl chloroformate. ¹ H NMR (DMSO-d ₆ ) δ ppm 0.80 (d, J = 6.9 Hz, 3H), 0.83 (d, J = 6.9 Hz, 3H), 0.96 (d, J = 6 .6 Hz, 6H), 1.94 (m, 2H), 3.59 (m, 1H), 3.93 (d, J = 6.6 Hz, 2H), 7.58 (dd, J = 8.5) , 1.9 Hz, 1H), 7.83 (dd, J = 8.5, 1.6 Hz, 1H), 8.03 (dbr, J = 8.5 Hz, 1H), 8.23 (d, = 1.9 Hz, 1H), 8.34 (d, J = 8.5 Hz, 1H), 8.38 (d, J = 8.5 Hz, 1H), 8.39 (d, J = 1.6 Hz, 1H) ), 10.00 (s, 1 H) and 12.49 (s br, 1 H); MS (ES +) 479.0.

Example 84: Preparation of (S) -2- (6-chloro-7- (methoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid As described in Examples 1 and 65 (S) -2- (6-Chloro-7- (methoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was prepared according to a procedure similar to that described above. ¹ H NMR (DMSO-d ₆ ) δ ppm 0.80 (d, J = 6.9 Hz, 3H), 0.83 (d, J = 6.6 Hz, 3H), 1.95 (m, 1H), 3.61 (m, 1H), 3.72 (s, 3H), 7.81 (d, J = 8.8 Hz, 1H), 7.91 (dd, J = 8.5, 1.6 Hz, 1H) ), 8.10 (m, 1H), 8.42 (d, J = 8.8 Hz, 1H), 8.50 (d, J = 8.5 Hz, 1H), 8.52 (d, J = 1) .3 Hz, 1 H), 9.46 (s, 1 H) and 12.45 (s br, 1 H); MS (ES +) 471.0.

Example 85: Preparation of (S) -2- (7- (isopropoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid The procedure described in Examples 1 and 65 was followed. According to a similar procedure, (S) -2- (7- (isopropoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was prepared using isopropyl chloroformate. _{^{1 H NMR (DMSO-d 6}} ) δ ppm 0.81 (d, J = 6.9Hz, 3H), 0.84 (d, J = 6.9Hz, 3H), 1.30 (d, J = 6 .2 Hz, 6H), 1.95 (m, 1H), 3.60 (dd, J = 9.5 6.0 Hz, 1H), 4.95 (dq, J = 6.2 6.2 Hz, 1H) 7.58 (dd, J = 8.7 1.9 Hz, 1H), 7.83 (dd, J = 8.3 1.6 Hz, 1H), 8.05 (d, J = 9.6 Hz, 1H) ), 8.23 (d, J = 1.8 Hz, 1H), 8.33 (d, J = 8.8 Hz, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.39. (D, J = 1.8 Hz, 1H), 9.96 (s, 1H) and 12.50 (sbr, 1H); MS (ES +) 465.1.

Example 86: Preparation of (S) -3-methyl-2- (7- (p-tolyloxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid As described in Examples 1 and 65 According to a procedure similar to that described above, using p-tolyl chloroformate and using (S) -3-methyl-2- (7- (p-tolyloxycarbonylamino) dibenzo [b, d] thiophene-3- Sulfonamido) butanoic acid was prepared. ¹ H NMR (DMSO-d ₆ ) δ ppm 0.81 (d, J = 6.9 Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H), 1.96 (m, 1H), 2.33 (s, 3H), 3.57 (m, 1H), 7.14 (d, J = 8.7 Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H), 7. 65 (dd, J = 9.1 2.5 Hz, 1H), 7.85 (dd, J = 8.7 1.7 Hz, 1H), 8.04 (s br, 1H), 8.25 (d, J = 1.9 Hz, 1H), 8.41 (m, 3H), 10.57 (sbr, 1H) and 12.52 (sbr, (1H); MS (ES +) 513.1.

Example 87: Preparation of (S) -2- (7-((4-fluorophenoxy) carbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid described in Examples 1 and 65 According to a procedure similar to that described, (S) -2- (7-((4-fluorophenoxy) carbonylamino) dibenzo [b, d] thiophene-3- Sulfonamido) -3-methylbutanoic acid was prepared. ¹ H NMR (DMSO-d ₆ ) δ ppm 0.81 (d, J = 6.9 Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H), 1.95 (m, 1H), 3.6 (m, 1H), 7.37-7.23 (m, 4H), 7.65 (dd, J = 8.7 1.8 Hz, 1H), 7.85 (dd, J = 8. 5 1.6 Hz, 1 H), 8.05 (d br, J = 9.5 Hz, 1 H), 8.25 (d, J = 1.9 Hz, 1 H), 8.41 (m, 3 H), 10. 63 (sbr, 1H) and 12.51 (sbr, 1H); MS (ES +) 517.1.

Example 88: Preparation of (S) -3-methyl-2- (7- (phenoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid The procedure described in Examples 1 and 65 was followed. (S) -3-Methyl-2- (7- (phenoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid was prepared using phenyl chloroformate according to a similar procedure. . ¹ H NMR (DMSO-d ₆ ) δ ppm 0.81 (d, J = 6.9 Hz, 3H), 0.85 (d, J = 6.9 Hz, 3H), 1.96 (m, 1H), 3.58 (m, 1H), 7.28 (d, J = 8.6 Hz, 2H), 7.29 (dd, J = 8.6 8.6 Hz, 1H), 7.46 (dd, J = 8.6 8.6 Hz, 2H), 7.66 (dd, J = 8.8 2.0 Hz, 1H), 7.85 (dd, J = 8.5 1.5 Hz, 1H), 8.02 ( sbr, 1H), 8.26 (d, J = 1.8 Hz, 1H), 8.41 (m, 3H), 10.62 (sbr, 1H) and 12.48 (sbr, 1H); MS (ES +) 499.0.

Example 89: Preparation of (S) -2- (7-((but-3-ynyloxy) carbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid Example 1 and 65 (S) -2- (7-((but-3-ynyloxy) carbonylamino) dibenzo [b, d] using but-3-ynylchloroformate following a procedure similar to that described. Thiophene-3-sulfonamido) -3-methylbutanoic acid was prepared. ¹ H NMR (DMSO-d ₆ ) δ ppm 0.80 (d, J = 6.9 Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H), 1.95 (m, 1H), 2.60 (dt, J = 6.4 2.6 Hz, 2H), 2.91 (t, J = 2.6 Hz, 1H), 3.60 (dd, J = 9.1 5.9 Hz, 1H) , 4.22 (t, J = 6.4 Hz, 2H), 7.60 (dd, J = 8.7 1.7 Hz, 1H), 7.84 (dd, J = 8.5 1.6 Hz, 1H) ), 8.05 (d br, J = 9.4 Hz, 1H), 8.24 (d, J = 1.7 Hz, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8. 39 (d, J = 8.0 Hz, 1H), 8.4 (d, J = 1.9 Hz, 1H), 10.14 (sbr, 1H) and 12.51 (sbr, 1H); MS ( ES + 475.1.

Example 90: Preparation of (S) -3-methyl-2- (7-((2- (methylsulfonyl) ethoxy) carbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid And (S) -3-methyl-2- (7-((2- (methylsulfonyl) ethoxy) using 2- (methylsulfonyl) ethyl chloroformate according to a procedure similar to that described in ) Carbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid was prepared. ¹ H NMR (DMSO-d ₆ ) δ ppm 0.80 (d, J = 6.9 Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H), 1.95 (m, 1H), 3.10 (s, 3H), 3.58 (m, 3H), 4.51 (dd, J = 6.01 6.01 Hz, 2H), 7.60 (dd, J = 8.4 1.9 Hz) , 1H), 7.84 (dd, J = 8.6 1.9 Hz, 1H), 8.01 (dbr, J = 9.1 Hz, 1H), 8.24 (d, J = 1.8 Hz, 1H), 8.42-8.34 (m, 3H), 10.16 (sbr, 1H) and 12.52 (sbr, 1H); MS (ES +) 529.1.

Example 91: Preparation of (S) -2- (7- (benzyloxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid The procedure described in Examples 1 and 65 was followed. Following a similar procedure, (S) -2- (7- (benzyloxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was prepared using benzyl chloroformate. ¹ H NMR (DMSO-d ₆ ) δ ppm 0.81 (d, J = 6.9 Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H), 1.95 (m, 1H), 3.60 (dd, J = 9.5, 5.9 Hz, 1H), 5.21 (s, 2H), 7.49-7.33 (m, 5H), 7.58 (dd, J = 8. 8 2.0 Hz, 1H), 7.84 (dd, J = 8.5 1.6 Hz, 1H), 8.06 (d, J = 9.3 Hz, 1H), 8.24 (d, J = 1) .7 Hz, 1H), 8.35 (d, J = 8.6 Hz, 1H), 8.39 (d, J = 8.0 Hz, 1H), 8.39 (d, J = 1.9 Hz, 1H) , 10.17 (sbr, 1H) and 12.52 (sbr, 1H); MS (ES +) 513.1.

Example 92: (R) -2- {7- [4- (2-hydroxy-ethyl)-[1,2,3] triazol-1-yl] -dibenzofuran-2-sulfonylamino} -3-methyl- Preparation of butyric acid Step 1: Preparation of (R) -2- (7-azido-dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid methyl ester (R) -2- (7 in 18% HCl (30 mL) - amino - dibenzofuran-2-sulfonylamino) -3-methyl - a suspension of butyric acid methyl ester (1.83 g, 5 mmol), cooled with an ice-water bath, NaNO ₂ aqueous solution (1.0 M, 7.5 mL ) Was added. After stirring for 20 minutes, aqueous sodium azide (1.0 M, 10 mL) was added and the resulting mixture was stirred at ambient temperature for 2 hours. The reaction was neutralized to about pH 6 with NaOH solution. The precipitate was collected by filtration to give 1.9 g of 2- (7-azido-dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid methyl ester. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.81 (d, 6H), 1.89 (d, 1H), 3.26 (d, 3H), 3.65 (d, 1H), 7 .24 (dd, J = 8.34, 2.02 Hz, 1H), 7.61 (d, J = 2.02 Hz, 1H), 7.86-7.90 (m, 2H), 8.35 ( d, J = 8.34 Hz, 1H) and 8.57 (d, J = 1.52 Hz, 1H).

Step 2: (R) -2- {7- [4- (2-hydroxy-ethyl)-[1,2,3] triazol-1-yl] -dibenzofuran-2-sulfonylamino} -3-methyl-butyric acid Preparation of methyl ester Suspension of 2- (7-azido-dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid methyl ester (200 mg, 0.5 mmol) in dimethyl sulfoxide and water (2 mL, 1: 1) Was added but-3-yn-1-ol (1.5 mmol), copper (II) sulfate (25 mg) and sodium L-ascorbate (250 mg). The reaction mixture is stirred at room temperature overnight, diluted with water, acidified to pH ˜3 with 1N HCl and filtered to give 195 mg of (R) -2- {7- [4- (2-hydroxy- Ethyl)-[1,2,3] triazol-1-yl] -dibenzofuran-2-sulfonylamino} -3-methyl-butyric acid methyl ester was obtained. ^{1 H NMR (400MHz, DMSO-} d 6) δ ppm 0.84 (t, J = 7.07Hz, 6H), 1.89-2.01 (m, 1H), 2.93 (t, J = 6 .69 Hz, 2H), 3.28 (s, 3H), 3.70 (d, J = 6.57 Hz, 1H), 3.78 (t, 2H), 7.89-8.06 (m, 3H) ), 8.32 (d, 1H), 8.48 (d, J = 8.34 Hz, 1H) and 8.66 (s, 1H).

Step 3: (R) -2- {7- [4- (2-hydroxy-ethyl)-[1,2,3] triazol-1-yl] -dibenzofuran-2-sulfonylamino} -3-methyl-butyric acid (R) -2- {7- [4- (2-hydroxy-ethyl)-[1,2,3] triazol-1-yl] -dibenzofuran-2-sulfonylamino} obtained from the previous step -3-Methyl-butyric acid methyl ester (195 mg) was suspended in water (4 mL) and THF (1 mL), and lithium hydroxide (230 mg, 10 mmol) was added. The resulting mixture was stirred at room temperature overnight, acidified with HCl to pH˜4, and filtered to give 161 mg of (R) -2- {7- [4- (2-hydroxy-ethyl)-[ 1,2,3] triazol-1-yl] -dibenzofuran-2-sulfonylamino} -3-methyl-butyric acid was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.82 (dd, J = 15.92, 6.57 Hz, 6H), 1.87-2.02 (m, 1H), 2.90 (t , 2H), 3.74 (t, 2H), 4.82 (d, 1H), 7.96 (d, 2H), 8.06 (s, 1H), 8.36 (d, J = 1. 77 Hz, 1H), 8.52 (d, J = 8.34 Hz, 1H), 8.66-8.69 (m, 1H) and 8.75 (s, 1H). MS (ES-): 457.1.

Example 93: Preparation of (R) -2- [7- (4-Isobutyl- [1,2,3] triazol-1-yl) -dibenzofuran-2-sulfonylamino] -3-methyl-butyric acid (R) -2- [7- (4-Isobutyl- [1,2,3] triazol-1-yl) -dibenzofuran-2-sulfonylamino] -3-methyl according to a procedure analogous to that described in -Butyric acid was prepared as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.79-1.01 (m, 12H), 1.24 (d, 2H), 1.91-2.08 (m, 1H), 2. 35-2.40 (m, 1H), 3.70 (d, 1H), 7.89-7.93 (m, 1H), 7.99 (dd, J = 8.59, 2.02 Hz, 1H ), 8.04 (dd, J = 8.46, 1.89 Hz, 1H), 8.32 (d, J = 1.77 Hz, 1H), 8.46 (d, J = 8.59 Hz, 1H) And 8.62 (s, 1H); MS (ES-) 469.2.

Example 94: Preparation of (R) -2- [7- (4-hydroxymethyl- [1,2,3] triazol-1-yl) -dibenzofuran-2-sulfonylamino] -3-methyl-butyric acid (R) -2- [7- (4-Hydroxymethyl- [1,2,3] triazol-1-yl) -dibenzofuran-2-sulfonylamino] -3 according to a procedure analogous to that described in 92. -Methyl-butyric acid was prepared as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.84 (dd, 6H), 1.87-2.03 (m, 1H), 3.54-3.68 (m, 1H), 4. 65 (d, J = 5.56 Hz, 2H), 7.92-8.00 (m, 1H), 8.07 (dd, J = 8.34, 2.02 Hz, 1H), 8.12 (d , J = 9.35 Hz, 1H), 8.39 (d, J = 2.02 Hz, 1H), 8.53 (d, J = 8.34 Hz, 1H), 8.66-8.70 (m, 1H) and 8.86 (s, 1H); MS (ES-) 443.1.

Example 95: Preparation of (R) -2- [7- (4-cyclohexyl- [1,2,3] triazol-1-yl) -dibenzofuran-2-sulfonylamino] -3-methyl-butyric acid (R) -2- [7- (4-Cyclohexyl- [1,2,3] triazol-1-yl) -dibenzofuran-2-sulfonylamino] -3-methyl according to a procedure analogous to that described in -Butyric acid was prepared as an off-white solid. ¹ H NMR (400 MHz, MeOD) δ ppm 1.84 (dd, J = 15.41, 6.82 Hz, 6H), 2.22-3.14 (m, 12H), 4.62 (d, 1H) 8.93-9.02 (m, 2H), 9.06 (dd, J = 8.46, 1.89 Hz, 1H), 9.37 (d, J = 2.02 Hz, 1H), 9. 54 (d, J = 8.34 Hz, 1H), 9.69 (d, J = 1.26 Hz, 1H) and 9.75 (s, 1H); MS (ES−) 495.2.

Example 96: (R) -1- [8- (1-carboxy-2-methyl-propylsulfamoyl) -dibenzofuran-3-yl] -1H- [1,2,3] triazole-4-carboxylic acid Following a procedure similar to that described in Example 92, (R) -1- [8- (1-carboxy-2-methyl-propylsulfamoyl) -dibenzofuran-3-yl] -1H- [ 1,2,3] triazole-4-carboxylic acid was prepared as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.83 (s, 6H), 1.85-2.06 (m, 1H), 3.60-3.71 (m, 1H), 7. 88-8.05 (m, 2H), 8.15 (s, 1H), 8.49 (s, 1H), 8.52-8.60 (m, 1H), 8.71 (s, 1H) And 9.57 (s, 1 H); MS (ES-) 457.1.

Example 97 Preparation of (R) -3-Methyl-2- [7- (4-phenyl- [1,2,3] triazol-1-yl) -dibenzofuran-2-sulfonylamino] -butyric acid Example 92 (R) -3-Methyl-2- [7- (4-phenyl- [1,2,3] triazol-1-yl) -dibenzofuran-2-sulfonylamino] according to a procedure analogous to that described in -Butyric acid was prepared as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-0.91 (m, 6H), 1.85-2.05 (m, 1H), 3.64 (dd, J = 9.47) , 5.94 Hz, 1H), 7.37-7.45 (m, 1H), 7.54 (t, J = 7.58 Hz, 1H), 7.93-8.02 (m, 3H), 8 .09-8.17 (m, 2H), 8.44 (d, J = 1.77 Hz, 1H), 8.59 (d, J = 8.59 Hz, 1H), 8.71 (d, J = 1.52 Hz, 1H) and 9.47 (s, 1H); MS (ES-) 489.1.

Example 98: Preparation of (R) -2- [7- (4-dimethylaminomethyl- [1,2,3] triazol-1-yl) -dibenzofuran-2-sulfonylamino] -3-methyl-butyric acid Following a procedure similar to that described in Example 92, (R) -2- [7- (4-dimethylaminomethyl- [1,2,3] triazol-1-yl) -dibenzofuran-2-sulfonylamino] -3-Methyl-butyric acid was prepared as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.82 (dd, 6H), 1.89-2.04 (m, 1H), 2.78-2.87 (m, 8H), 3. 63 (dd, J = 9.60, 6.06 Hz, 1H), 7.94-8.03 (m, 1H), 8.07 (dd, J = 8.46, 1.89 Hz, 1H), 8 .15 (d, J = 9.60 Hz, 1H), 8.42 (d, J = 1.77 Hz, 1H), 8.59 (d, J = 8.34 Hz, 1H), 8.72 (d, J = 1.77 Hz, 1H) and 9.13 (s, 1H); MS (ES-) 470.2.

Example 99: Preparation of (S) -3-methyl-2- (8- (2-oxooxazolidin-3-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid Step 1: (S) Preparation of -tert-butyl 2- (8-((2-bromoethoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (S) -tert-butyl 2- (8-aminodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (1.105 g, 2.64 mmol) and DMAP (0.387 g, 3.17 mmol) in 30 mL CH ₂ Cl It was dissolved in _2, 2-bromoethyl chloroformate (0.55 g, 2.9 mmol) was added. The mixture was stirred at room temperature overnight, concentrated and purified by silica gel column chromatography to give (S) -tert-butyl 2- (8-((2-bromoethoxy) carbonylamino) dibenzo [b, d]. Furan-3-sulfonamido) -3-methylbutanoate was obtained as a gray solid in 95% yield.

Step 2: Preparation of (S) -tert-butyl 3-methyl-2- (8- (2-oxooxazolidin-3-yl) dibenzo [b, d] furan-3-sulfonamido) butanoate in 10 mL DMF (S) -tert-butyl 2- (8-((2-bromoethoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (1) obtained from step 1 .36 g, 2.4 mmol) was mixed with potassium carbonate (1 g, 0.72 mol). The reaction mixture was stirred for 18 hours and purified by preparative HPLC to give (S) -tert-butyl 3-methyl-2- (8- (2-oxooxazolidin-3-yl) dibenzo [b, d] Furan-3-sulfonamido) butanoate was obtained as a pale yellow solid in 92% yield.

Step 3: Preparation of (S) -3-methyl-2- (8- (2-oxooxazolidin-3-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid sulfone obtained from Step 2 amide t- butyl ester (1.03 g, 2.1 mmol) and 20mL of _{TFA / CH 2 Cl 2 (1} : 1) were mixed and stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue was triturated in CH ₃ CN / H ₂ O followed by a lyophilization process. (S) -3-Methyl-2- (8- (2-oxooxazolidin-3-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid was obtained as a pale yellow solid in 99% yield. It was. _{HRMS: [C 20 H 20 N} 2 O 7 S + H] + calcd 433.10640 for; found ^{(ESI-FTMS, [M +} H] 1+) 433.10635.

Example 100: Preparation of (S) -2- (8- (diethylamino) dibenzo [b, d] furan-3-sulfonamido) 3-methylbutanoic acid Step 1: (S) -tert-Butyl 2- (8- (Diethylamino) dibenzo [b, d] furan-3-sulfonamido) 3-methylbutanoate and (S) -tert-butyl 2- (8- (ethylamino) dibenzo [b, d] furan-3-sulfone Preparation of (amido) 3-methylbutanoate (S) -tert-Butyl 3-methyl-2- (8-nitrodibenzo [b, d] furan-3-sulfonamido) butanoate (560 mg) and 200 mg Pd / C (10%) was mixed with 150 mL MeOH and 2 mL CH ₃ CN. The reaction was performed in a Parr shaker at room temperature overnight under hydrogen (50 psi). The reaction mixture was filtered through Celite®. By separating the reaction mixture, 292 mg of (S) -tert-butyl 2- (8- (diethylamino) dibenzo [b, d] furan-3-sulfonamido) 3-methylbutanoate and 235 mg of (S) -Tert-Butyl 2- (8- (ethylamino) dibenzo [b, d] furan-3-sulfonamido) 3-methylbutanoate were both obtained as a yellow solid.

Step 2: Preparation of (S) -2- (8- (diethylamino) dibenzo [b, d] furan-3-sulfonamido) 3-methylbutanoic acid Sulfonamide t- of the diethylated compound obtained from Step 1 Butyl ester (126 mg) was mixed in 2 mL TFA / CH ₂ Cl ₂ (1: 1) and stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue was triturated with CH ₃ CN / H ₂ O followed by a lyophilization process. (S) -2- (8- (Diethylamino) dibenzo [b, d] furan-3-sulfonamido) 3-methylbutanoic acid was obtained as a white solid in 95% yield. _{HRMS: [C 21 H 26 N} 2 O 5 S + H] + calcd 419.16352 for; found (ESI-FTMS, [M + H] 1+) 419.16354.

Example 101 Preparation of (S) -2- (8- (Ethylamino) dibenzo [b, d] furan-3-sulfonamido) 3-methylbutanoic acid Diethylated t-butyl in Step 2 of Example 100 Similar to the ester, (S) -tert-butyl 2- (8- (ethylamino) dibenzo [b, d] furan-3-sulfonamido) 3-methylbutanoate (Example 100, Step 1, 58 mg) ) Was processed. (S) -2- (8- (ethylamino) dibenzo [b, d] furan-3-sulfonamido) 3-methylbutanoic acid (50.6 mg) was obtained as a white solid in quantitative yield. _{HRMS: [C 19 H 22 N} 2 O 5 S + H] + calcd 391.13222 for; found ^{(ESI-FTMS, [M +} H] 1+) 391.13198.

Example 102: Preparation of (S) -2- (8- (ethyl (methoxycarbonyl) amino) dibenzo [b, d] furan-3-sulfonamido) 3-methylbutanoic acid Step 1: (S) -tert-butyl Preparation of 2- (8- (ethyl (methoxycarbonyl) amino) dibenzo [b, d] furan-3-sulfonamido) 3-methylbutanoate (S) -tert-butyl 2- (8- (ethylamino) Dibenzo [b, d] furan-3-sulfonamido) 3-methylbutanoate (Example 100, Step 1, 122 mg, 0.27 mmol) and DMAP (40 mg, 0.33 mmol) in 3 mL of CH ₂ Cl ₂ After dissolution, methyl chloroformate (31 mg, 0.33 mmol) was added. The mixture is stirred at room temperature overnight, concentrated and purified by silica gel column chromatography to give (S) -tert-butyl 2- (8- (ethyl (methoxycarbonyl) amino) dibenzo [b, d] furan- 3-sulfonamido) 3-methylbutanoate was obtained as a white solid in 95% yield.

Step 2: Preparation of (S) -2- (8- (Ethyl (methoxycarbonyl) amino) dibenzo [b, d] furan-3-sulfonamido) 3-methylbutanoic acid Sulfonamide t-butyl obtained from Step 1 The ester (100 mg) was mixed with 1 mL of TFA / CH ₂ Cl ₂ (1: 1) and stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue was triturated in CH ₃ CN / H ₂ O followed by a lyophilization process to give 96 mg of (S) -2- (8- (ethyl (methoxycarbonyl) amino) Dibenzo [b, d] furan-3-sulfonamido) 3-methylbutanoic acid was obtained as a white solid in quantitative yield. _{HRMS: [C 21 H 24 N} 2 O 7 S + H] + calcd 449.13770 for; found ^{(ESI-FTMS, [M +} H] 1+) 449.1379.

Example 103 Preparation of (S) -3-Methyl-2- (8-morpholinodibenzo [b, d] furan-3-sulfonamido) butanoic acid Step 1: 8-Bromodibenzo [b, d] furan-3 Preparation of sulfonyl chloride Dibenzo [b, d] furan-3-sulfonyl chloride (5.3 g) was mixed with AcOH (glacial acetic acid, 120 mL) and bromine (10 eq, 10 mL). The mixture was stirred at 70 ° C. for 4 hours. Excess bromine was removed by bubbling nitrogen through the reaction mixture. The reaction mixture was cooled to room temperature and filtered to give 5.4 g of 8-bromodibenzo [b, d] furan-3-sulfonyl chloride as a light brown solid.

Step 2: Preparation of (S) -tert-butyl 2- (8-bromodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate 8-bromodibenzo [b, d] furan-3 - sulfonyl chloride (3.46 g, 10 mmol) and (S)-tert-butyl 2-amino-3-methylbutanoate hydrochloride (2.3 g, 1.1 eq) was mixed with _CH 2 Cl ₂ in 30mL To this was added N, N-diisopropylethylamine (3.84 mL, 2.2 eq). The mixture was stirred at room temperature for 5 hours and purified by column chromatography to give 4.7 g (S) -tert-butyl 2- (8-bromodibenzo [b, d] furan-3-sulfonamido) -3- Methyl butanoate was obtained as a white solid.

Step 3: Preparation of (S) -tert-butyl 3-methyl-2- (8-morpholinodibenzo [b, d] furan-3-sulfonamido) butanoate (S) -tert-butyl 2- (8-bromodibenzo [B, d] furan-3-sulfonamido) -3-methylbutanoate (240 mg, 0.5 mmol), 2- (dicyclohexylphosphino) biphenyl (120 mg), morpholine (104 mg, 2.4 equivalents), phosphorus Tripotassium acid (K ₃ PO ₄ , 320 mg) and tris (dibenzylideneacetone) dipalladium (0) (Pd ₂ (dba) ₃ , 30 mg) were mixed with 4 mL of dioxane. Oxygen was removed from the mixture using nitrogen gas and stirred at 90 ° C. overnight. The reaction mixture was mixed with brine and extracted with EtOAc. Removal of the solvent gave a crude product which was purified by column chromatography to obtain 16 mg of (S) -tert-butyl 3-methyl-2- (8-morpholinodibenzo [b, d] furan. -3-Sulfonamido) butanoate was obtained as a white solid.

Step 4: Preparation of (S) -2- (8- (6-methoxypyridin-3-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid (S) -tert-butyl 2 -(8- (6-Methoxypyridin-3-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (16 mg) was added to 2 mL of TFA / CH ₂ Cl ₂ (1: 1 ). The solution was stirred at room temperature for 3 hours, concentrated under reduced pressure, the residue was triturated with CH ₃ CN / H ₂ O and then subjected to a lyophilization process to give 11 mg of (S) -3-methyl-2- ( 8-morpholinodibenzo [b, d] furan-3-sulfonamido) butanoic acid was obtained as a white solid. _{HRMS: [C 21 H 24 N} 2 O 6 S + H] + calcd 433.14278 for; found ^{(ESI-FTMS, [M +} H] 1+) 433.1425.

Example 104: (S) -3-Methyl-2- (8- (3- (trifluoromethyl) -1H-pyrazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid Preparation Step 1: (S) -tert-butyl 3-methyl-2- (8- (3- (trifluoromethyl) -1H-pyrazol-1-yl) dibenzo [b, d] furan-3-ylsulfonamide ) Preparation of butanoate (S) -tert-butyl 2- (8-bromodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (Example 103, Step 2, 485 mg, 1 mmol), 3- (trifluoromethyl) pyrazole (274 mg, 2 mmol), trans-N, N′-dimethyl-1,2-cyclohexanediamine (29 mg, 0.2 mmol), copper iodide ( ) (Mixing CuI, 10 mg, 0.05 mmol) and _{K 3 PO 4 (450mg, 21mmol} ) the in toluene 2 mL. The mixture was irradiated with microwave at 130 ° C. for 3 hours. The reaction mixture was purified by preparative HPLC to give 313 mg (S) -tert-butyl 3-methyl-2- (8- (3- (trifluoromethyl) -1H-pyrazol-1-yl) dibenzo [b , D] furan-3-ylsulfonamido) butanoate as a white solid in 58% yield.

Step 2: Preparation of (S) -3-methyl-2- (8- (3- (trifluoromethyl) -1H-pyrazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid The sulfonamide t-butyl ester obtained from step 1 (100 mg) was mixed in 1 mL TFA / CH ₂ Cl ₂ (1: 1) and stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue was triturated in CH ₃ CN / H ₂ O followed by a lyophilization process to give 96 mg of (S) -3-methyl-2- (8- (3- ( Trifluoromethyl) -1H-pyrazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid was obtained as a white solid in quantitative yield. _{HRMS: [C 21 H 18 F} 3 N 3 O 5 S + H] + calcd 482.09920 for; found ^{(ESI-FTMS, [M +} H] 1+) 482.09983.

Example 105: Preparation of (S) -2- (8- (1H-pyrazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Step 1: (S) -tert Preparation of -butyl 2- (8- (1H-pyrazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (S) -tert-butyl 2- (8- Bromodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (200 mg, 0.4 mmol), pyrazole (56 mg, 0.8 mmol), trans-N, N′-dimethyl-1,2, - cyclohexanediamine (12mg, 0.08mmol), mixed with CuI (4mg, 0.02mmol) and _{K 3 PO 4 (185mg, 0.87mmol} ) of 2mL of toluene did. The mixture was irradiated with microwave at 130 ° C. for 3 hours. The reaction mixture was purified by preparative HPLC to give 40 mg of (S) -tert-butyl 2- (8- (1H-pyrazol-1-yl) dibenzo [b, d] furan-3-sulfonamide) -3 -Methylbutanoate was obtained as a white solid in 20% yield.

Step 2: Preparation of (S) -2- (8- (1H-pyrazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid sulfonamide t obtained from Step 1 - butyl ester (100 mg) of _{0.5mL TFA / CH 2 Cl 2 (} 1: 1) were mixed in and stirred for 4 hours at room temperature. The solvent was removed under reduced pressure and the residue was triturated in CH ₃ CN / H ₂ O followed by lyophilization process to give 23 mg of (S) -2- (8- (1H-pyrazol-1-yl ) Dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid was obtained as a white solid in quantitative yield. _{HRMS: [C 20 H 19 N} 3 O 5 S + H] + calcd 414.11182 for; we found ^{(ESI-FTMS, [M +} H] 1+) 414.11215.

Example 106: Preparation of (S) -3-methyl-2- (8- (piperazin-1-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid Step 1: (S) -tert- Preparation of butyl 4- (7- (N- (1-tert-butoxy-3-methyl-1-oxobutan-2-yl) sulfamoyl) dibenzo [b, d] furan-2-yl) piperazine-1-carboxylate (S) -tert-butyl 2- (8-bromodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (320 mg, 0.66 mol), tert-butyl 1-piperazinecarboxylate ( _{247mg, 1.32mmol), Pd 2 (} dba) 3 (14mg, 0.01mmol), tri (o-tolyl) phosphine (8 mg, 0.04 mmol) Contact Fine sodium tert- butoxide (140 mg, 1.45 mmol) were mixed in toluene in 2 mL, and stirred for 18 hours at 110 ° C.. The reaction mixture was purified by preparative HPLC to give 54 mg (S) -tert-butyl 4- (7- (N- (1-tert-butoxy-3-methyl-1-oxobutan-2-yl) sulfamoyl) Dibenzo [b, d] furan-2-yl) piperazine-1-carboxylate was obtained as a white solid in 14% yield.

Step 2: Preparation of (S) -3-Methyl-2- (8- (piperazin-1-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid Sulfonamide t-obtained from Step 1 Butyl ester (50 mg) was mixed in 0.5 mL TFA / CH ₂ Cl ₂ (1: 1) and stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue was triturated in CH ₃ CN / H ₂ O followed by a lyophilization process to give 36 mg of (S) -3-methyl-2- (8- (piperazine-1 -Yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid was obtained as a white solid in quantitative yield. MS (LCMS-ESI) 432.3.

Example 107: Preparation of (S) -2- (8- (1H-imidazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Step 1: (S) -tert -Preparation of butyl 2- (8- (1H-imidazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (S) -tert- in MeOH (10 mL) Butyl 2- (8-aminodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (418 mg, 1 mmol) was added in 40% aqueous glyoxal (160 mg, 1.1 mmol) at room temperature for 16 hours. Was processed. Ammonium chloride (106 mg, 2 mmol) was added followed by 37% formaldehyde aqueous solution (162 mg, 2 mmol). The mixture was diluted with 20 mL MeOH and the resulting mixture was heated to reflux for 1 h. Phosphoric acid (1 mL) was added dropwise and the mixture was heated to reflux for an additional 4-8 hours. The reaction mixture was mixed with water and neutralized to pH 9 with aqueous NaOH. The mixture was extracted with CH ₂ Cl ₂ . By concentrating the combined organic layers, a crude product was obtained, which was purified by column chromatography to obtain 160 mg of (S) -tert-butyl 2- (8- (1H-imidazol-1-yl). Dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate was obtained as a light brown oil.

Step 2: Preparation of (S) -2- (8- (1H-imidazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid sulfonamide t obtained from Step 1 - butyl ester (0.2 mmol) of 2mL _TFA / CH ₂ Cl _2: was dissolved in (1 1). The solution was stirred at room temperature for 3 hours, concentrated under reduced pressure, and the residue was triturated with CH ₃ CN / H ₂ O followed by a lyophilization process. (S) -2- (8- (1H-imidazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid was obtained as a white solid in 95% yield. _{HRMS: [C 20 H 19 N} 3 O 5 S + H] + calcd 414.11182 for; found ^{(ESI-FTMS, [M +} H] 1+) 414.11231.

Example 108: Preparation of (S) -2- (8- (4,5-dimethyl-1H-imidazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid (S) -2- (8- (4,5-Dimethyl-1H-imidazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) — following a procedure analogous to that described in 107 3-methylbutanoic acid was prepared as an off-white solid. _{HRMS: [C 22 H 23 N} 3 O 5 S + H] + calcd 442.14312 for; found (ESI-FTMS, [M + H]) 442.1443.

Example 109: (R) -3-methyl-2- (7- (4-((trimethylsilyl) methyl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] furan-2 Preparation of -sulfonamido) butanoic acid Following a procedure similar to that described in Example 92 and using trimethyl (prop-2-ynyl) silane, (R) -3-methyl-2- (7- ( 4-((Trimethylsilyl) methyl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] furan-2-sulfonamido) butanoic acid was obtained as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.60 (d, J = 1.26 Hz, 1H), 8.49 (s, 1H), 8.44 (d, J = 8.08 Hz, 1H) ), 8.29 (d, J = 2.27 Hz, 1H), 8.05 (d, J = 9.60 Hz, 1H), 7.98 (dd, J = 8.46, 1.89 Hz, 1H) , 7.85-7.93 (m, 2H), 3.52-3.58 (m, 1H), 1.83-1.94 (m, 1H), 0.75 (dd, 6H) and-. 0.01-0.01 (m, 9H); MS (LCMS-ESI, M + H) 501.24.

Example 110: (S) -2- (8- (4-cyclohexyl-1H-1,2,3-triazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Step 1: Preparation of (S) -methyl 3-methyl-2- (8-nitrodibenzo [b, d] furan-3-sulfonamido) butanoate L-valine methyl ester (HCl salt, 6.44 g, 35 7 mmol) and di-isopropylethylamine (8.6 g, 10 mL) in CH ₂ Cl ₂ (100 mL) to give 8-nitrodibenzo [b, d] furan-3-sulfonyl chloride (Example 28) (9 .57 g, 35.7 mmol) was added in portions at 0 ° C. The reaction was warmed to room temperature over 2 hours. Water (200 mL) was added and CH ₂ Cl ₂ was removed under reduced pressure. The resulting suspension is filtered and the filter cake is washed with water and dried to give 14.0 g of (S) -methyl 3-methyl-2- (8-nitrodibenzo [b, d] furan- 3-sulfonamido) butanoate was obtained in a yield of 97%.

Step 2: Preparation of (S) -methyl 2- (8-aminodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate Obtained from step 1 in MeOH (150 mL) ( S) -methyl 3-methyl-2- (8-nitrodibenzo [b, d] furan-3-sulfonamido) butanoate (14 g) and 0.5 g of 10% Pd / C (50% water) under hydrogen ( 50 psi) for 16 hours in a Parr shaker. The suspension was filtered through Celite®. Concentration of the filtrate yielded 99% yield of 13.5 g of (S) -methyl 2- (8-aminodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate as a white solid. Obtained at a rate.

Step 3: Preparation of (S) -methyl 2- (8-azidodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate Obtained from step 2 in 18% HCl (60 mL). A suspension of (S) -methyl 2- (8-aminodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (3.62 g, 10 mmol) was added using an ice-water bath. Cool and add aqueous sodium nitrite (1.0 M, 16 mL). The resulting reaction was stirred for 20 minutes, to which sodium azide solution (1.0 M, 20 mL) was added. The resulting mixture is stirred at ambient temperature for 3 hours, neutralized to a pH of about 6 with sodium hydroxide solution and filtered to give (S) -methyl 2- (8-azidodibenzo [b, d] furan. -3-Sulfonamido) -3-methylbutanoate (3.0 g) was obtained.

Step 4: (S) -Methyl 2- (8- (4-cyclohexyl-1H-1,2,3-triazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbuta Preparation of noate (S) -methyl 2- (8-azidodibenzo [b, d] furan-3-sulfonamido) -3-methyl obtained from step 3 in DMSO (1 mL) and water (1 mL). To a suspension of butanoate (200 mg, 0.5 mmol) was added ethynylcyclohexane (0.5 mmol), copper sulfate (25 mg) and sodium L-ascorbate (250 mg). The reaction mixture is stirred overnight at room temperature, diluted with water, acidified with 1N HCl to pH˜2, and filtered to give (S) -methyl 2- (8- (4-cyclohexyl-1H-1,2). , 3-Triazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (225 mg).

Step 5: (S) -2- (8- (4-Cyclohexyl-1H-1,2,3-triazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid (S) -Methyl 2- (8- (4-cyclohexyl-1H-1,2,3-triazol-1-yl) dibenzo [b, d] furan-3-sulfonamide)-obtained from Preparation Step 4 3-Methylbutanoate (225 mg) was suspended in water (4 mL) and THF (1 mL). To the mixture was added lithium hydroxide (230 mg, 10 mmol). The reaction mixture was stirred at room temperature overnight and acidified with hydrochloric acid to pH˜2. The precipitate was collected by filtration to give (S) -2- (8- (4-cyclohexyl-1H-1,2,3-triazol-1-yl) dibenzo [b, d] furan-3-sulfonamide) -3-Methylbutanoic acid (180 mg) was obtained as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.83 (d, J = 2.53 Hz, 1 H), 8.64 (s, 1 H), 8.42 (d, J = 8.34 Hz, 1 H ), 8.10-8.16 (m, 2H), 8.01 (d, J = 9.09 Hz, 1H), 7.84-7.90 (m, 1H), 3.58-3.67. (M, 1H), 2.01-2.13 (m, 3H), 1.89-2.02 (m, 1H), 1.20-1.86 (m, 8H) and 0.83 (dd , 6H); MS (LCMS-ESI, M + H) 497.40.

Example 111: (S) -2- (8- (4- (2-hydroxyethyl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] furan-3-sulfonamide) Preparation of -3-methylbutanoic acid Following a procedure similar to that described in Example 110, using but-3-yn-1-ol instead of ethynylcyclohexane, (S) -2- (8- ( 4- (2-Hydroxyethyl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid was obtained as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.83 (d, J = 1.77 Hz, 1H), 8.65 (s, 1H), 8.43 (d, J = 8.08 Hz, 1H) ), 8.08-8.16 (m, 2H), 8.01 (d, J = 9.35 Hz, 1H), 7.87 (dd, J = 8.08, 1.52 Hz, 1H), 3 .74 (t, 2H), 3.45-3.57 (m, 1H), 2.90 (t, J = 6.82 Hz, 2H), 1.89-2.03 (m, 1H) and 0 .82 (dd, J = 19.96, 6.82 Hz, 6H); MS (LCMS-ESI, M + H) 459.30.

Example 112: (S) -2- (8- (4-((dimethylamino) methyl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] furan-3-sulfonamide ) -3-Methylbutanoic acid preparation Following procedures similar to those described in Example 110, using N, N-dimethylprop-2-yn-1-amine, (S) -2- (8- (4-((Dimethylamino) methyl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid is obtained as an off-white solid. It was. ^{1 H NMR (400MHz, MeOD)} δ ppm 9.06 (s, 1H), 8.87 (d, J = 2.27Hz, 1H), 8.53 (d, J = 8.08Hz, 1H), 8 .39 (s, 1H), 8.28-8.34 (m, 1H), 8.14 (d, J = 8.84 Hz, 2H), 4.92-5.18 (m, 6H), 3 .67-3.73 (m, 1H), 3.16-3.26 (m, 2H) and 1.16 (dd, 6H); MS (LCMS-ESI, M + H) 472.20.

Example 113: (S) -3-Methyl-2- (8- (4-phenyl-1H-1,2,3-triazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) butane Acid Preparation Following a procedure similar to that described in Example 110, using ethynylbenzene, (S) -3-methyl-2- (8- (4-phenyl-1H-1,2,3- Triazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid was obtained as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.39 (s, 1H), 8.90 (d, J = 2.27 Hz, 1H), 8.44 (d, J = 8.08 Hz, 1H) ), 8.19 (dd, J = 8.84, 2.27 Hz, 1H), 8.13-8.17 (m, 1H), 8.07 (d, J = 9.09 Hz, 1H), 7 .94-8.02 (m, 2H), 7.88 (dd, J = 8.21, 1.39 Hz, 1H), 7.53 (t, J = 7.58 Hz, 2H), 7.37- 7.45 (m, 1H), 3.42-3.54 (m, 1H), 1.91-2.03 (m, 1H) and 0.83 (dd, J = 22.86, 6.69 Hz) , 6H); MS (LCMS-ESI, M + H) 491.30.

Example 114: (S) -2- (8- (4-isobutyl-1H-1,2,3-triazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Following a procedure similar to that described in Example 110 and using 4-methylpent-1-yne, (S) -2- (8- (4-isobutyl-1H-1,2,3- Triazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid was obtained as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.71 (s, 1H), 8.57 (s, 1H), 8.40 (d, 1H), 8.06-8.18 (m, 2H), 8.00 (d, 1H), 7.88 (d, 1H), 1.84-2.13 (m, 1H), 1.21 (d, 2H), 0.97 (d, 6H) ) And 0.66-0.91 (m, 6H); MS (LCMS-ESI, M + H) 471.40.

Example 115: (S) -3-methyl-2- (7- (4- (1-methyl-1H-pyrrol-2-yl) -1H-1,2,3-triazol-1-yl) dibenzo [ Preparation of b, d] thiophene-3-sulfonamido) butanoic acid Step 1: Preparation of (S) -methyl 3-methyl-2- (7-nitrodibenzo [b, d] thiophene-3-sulfonamido) butanoate -Nitrodibenzo [b, d] thiophene-3-sulfonyl chloride (Example 65, Step 2, 599 mg, 1.83 mmol) and (S) -methyl 2-amino-3-methylbutanoate hydrochloride (335 mg, 2 0.0 mmol) was mixed with 5 mL of CH ₂ Cl ₂ , followed by the slow addition of N, N-diisopropylethylamine (520 mg, 4 mmol) at 0 ° C. The mixture was warmed to room temperature over 4 hours and purified by column chromatography to give (S) -methyl 3-methyl-2- (7-nitrodibenzo [b, d] thiophene-3-sulfonamido) butanoate as a white solid Obtained in 80% yield.

Step 2: Preparation of (S) -methyl 2- (7-aminodibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate (S) -methyl 3-methyl-2- (7- Nitrodibenzo [b, d] thiophene-3-sulfonamido) butanoate was mixed with MeOH and treated with hydrogen (40 psi) in the presence of 10% Pd / C (10% w / w) overnight. After removing the catalyst by filtration and removing the solvent, (S) -methyl 2- (7-aminodibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate was quantitatively recovered. Obtained at a rate.

Step 3: Preparation of (S) -methyl 2- (7-azidodibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate Obtained from step 2 in 18% HCl (60 mL). A suspension of (S) -methyl 2- (7-aminodibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate (3.93 g, 10 mmol) was cooled in an ice-water bath, Aqueous sodium nitrite (1.0 M, 16 mL) was added. The resulting solution was stirred for 20 minutes and to this was added aqueous sodium azide (1.0 M, 20 mL). The reaction mixture is stirred at ambient temperature for 3 hours, neutralized to pH ˜6 with sodium hydroxide solution and filtered to give (S) -methyl 2- (7-azidodibenzo [b, d] thiophene-3. -Sulfonamido) -3-methylbutanoate was obtained as an off-white solid.

Step 4: (S) -Methyl 3-methyl-2- (7- (4- (1-methyl-1H-pyrrol-2-yl) -1H-1,2,3-triazol-1-yl) dibenzo [ Preparation of b, d] thiophene-3-sulfonamido) butanoate (S) -methyl 2- (7-azidodibenzo [b, d] thiophene obtained from step 3 in DMSO (1 mL) and water (1 mL). To a suspension of -3-sulfonamido) -3-methylbutanoate (209 mg, 0.5 mmol) was added 2-ethynyl-1-methyl-1H-pyrrole (0.5 mmol), copper sulfate (25 mg) and L -Sodium ascorbate (250 mg) was added. The reaction mixture is stirred at room temperature overnight, diluted with water, acidified with 1N HCl and filtered to give (S) -methyl 3-methyl-2- (7- (4- (1-methyl-1H). -Pyrrol-2-yl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) butanoate was obtained as an off-white solid in 60% yield. .

Step 5: (S) -3-Methyl-2- (7- (4- (1-methyl-1H-pyrrol-2-yl) -1H-1,2,3-triazol-1-yl) dibenzo [b , D] Preparation of thiophene-3-sulfonamido) butanoic acid (S) -methyl 3-methyl-2- (7- (4- (1-methyl-1H-pyrrol-2-yl) obtained from step 4 -1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) butanoate (225 mg) was suspended in water (4 mL) and THF (1 mL) and lithium hydroxide ( 230 mg, 10 mmol) was added. The resulting mixture was stirred at room temperature overnight, acidified with hydrochloric acid to pH ˜4, and filtered to give (S) -3-methyl-2- (7- (4- (1-methyl-1H— Pyrrole-2-yl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid was obtained as an off-white solid in 90% yield. . MS (ES +) 510.24.

  (S) -3-Methyl-2- (7- (4- (1-methyl-1H-pyrrol-2-yl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] The sodium salt was prepared by treating thiophene-3-sulfonamido) butanoic acid with 1.0 equivalent of NaOH. The salt was obtained as a white solid.

Example 116: (S) -3-Methyl-2- (7- (4-phenyl-1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) butane Acid Preparation Following a procedure similar to that described in Example 115, using ethynylbenzene, (S) -3-methyl-2- (7- (4-phenyl-1H-1,2,3- Triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid was obtained. MS (ES +) 507.10.

Example 117: (S) -2- (7- (4-cyclohexyl-1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid The preparation of (S) -2- (7- (4-cyclohexyl-1H-1,2,3-triazol-1-yl) was carried out using ethynylcyclohexane according to a procedure similar to that described in Example 115. ) Dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.56-8.77 (m, 4H), 8.52 (d, J = 1.5 Hz, 1H), 8.12 (dd, J = 8 .8, 2.1 Hz, 1H), 7.91 (dd, J = 8.4, 1.3 Hz, 1H), 3.58 (d, J = 5.0 Hz, 1H), 2.65-2. 91 (m, 1H), 1.87-2.18 (m, 3H), 1.65-1.87 (m, 3H), 1.23-1.56 (m, 5H), 0.85 ( d, J = 6.7 Hz, 3H) and 0.81 (d, J = 6.7 Hz, 3H); MS (ES +) 513.16.

Example 118: (S) -2- (7- (4- (methoxymethyl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamide) -3 -Preparation of methylbutanoic acid According to a procedure similar to that described in Example 115 and using 3-methoxyprop-1-yne, (S) -2- (7- (4- (methoxymethyl) -1H- 1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.94 (s, 1H), 8.74 (d, J = 1.8 Hz, 1H), 8.68 (d, J = 8.8 Hz, 1H) ), 8.62 (d, J = 8.2 Hz, 1H), 8.14 (dd, J = 8.5, 2.1 Hz, 2H), 7.92 (dd, J = 8.5, 1.. 8 Hz, 1H), 4.60 (s, 2H), 3.63 (s, 1H), 3.36 (s, 3H), 1.79-2.11 (m, 1H), 0.85 (d , J = 6.7 Hz, 3H) and 0.81 (d, J = 6.7 Hz, 3H); MS (ES +) 475.12.

Example 119: (S) -2- (7- (4-tert-butyl-1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) -3- Preparation of methylbutanoic acid (S) -2- (7- (4-tert-butyl-1H) using 3,3-dimethylbut-1-yne according to a procedure similar to that described in Example 115. -1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.73 (s, 1H), 8.70 (d, J = 1.8 Hz, 1H), 8.66 (d, J = 8.5 Hz, 1H) ), 8.60 (d, J = 8.2 Hz, 1H), 8.52 (d, J = 1.2 Hz, 1H), 8.13 (dd, J = 8.8, 2.1 Hz, 1H) 7.92 (dd, J = 8.4, 1.6 Hz, 1H), 3.62 (d, J = 5.3 Hz, 1H), 1.83 to 2.09 (m, 1H), 1. 39 (s, 9H), 0.85 (d, J = 7.0 Hz, 3H) and 0.81 (d, J = 7.0 Hz, 3H); MS (ES +) 487.17.

Example 120: (S) -2- (7- (4-((dimethylamino) methyl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamide ) -3-Methylbutanoic acid preparation Following procedures similar to those described in Example 115, using N, N-dimethylprop-2-yn-1-amine, (S) -2- (7- (4-((Dimethylamino) methyl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was prepared. ¹ H NMR (300 MHz, MeOD) δ ppm 8.53-8.64 (m, 3H), 8.46-8.52 (m, 2H), 8.09 (d, J = 8.8 Hz, 1H) , 8.01 (dd, J = 8.5, 1.5 Hz, 1H), 4.61 (s, 2H), 3.77 (d, J = 5.9 Hz, 1H), 3.02 (s, 6H), 2.01-2.18 (m, 1H), 0.99 (d, J = 6.7 Hz, 3H) and 0.93 (d, J = 6.7 Hz, 3H); MS (ES +) 488.18.

Example 121: (S) -2- (7- (4- (hydroxymethyl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamide) -3 -Preparation of methylbutanoic acid Following a procedure similar to that described in Example 115 and using prop-2-yn-1-ol, 2- (7- (4- (hydroxymethyl) -1H-1, 2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.53 (br.s., 1H), 8.81 (s, 2H), 8.73 (d, J = 2.1 Hz, 1H), 8 .67 (d, J = 8.5 Hz, 1H), 8.61 (d, J = 8.5 Hz, 1H), 8.53 (d, J = 1.5 Hz, 1H), 8.14 (dd, J = 8.5, 2.1 Hz, 1H), 8.10 (br.s., 1H), 7.92 (dd, J = 8.2, 1.8 Hz, 1H), 4.66 (d, J = 5.0 Hz, 2H), 3.56-3.71 (m, J = 7.3, 5.9 Hz, 1H), 1.85-2.06 (m, 1H), 0.85 (d , J = 6.7 Hz, 3H) and 0.82 (d, J = 6.7 Hz, 3H); MS (ES +) 461.12.

Example 122: (S) -2- (7- (4- (methoxycarbonyl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamide) -3 Preparation of methylbutanoic acid Following a procedure similar to that described in Example 115 and using methyl propiolate, (S) -2- (7- (4- (methoxycarbonyl) -1H-1,2, 3-Triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was prepared. ^{1 H NMR (300MHz, DMSO-} d 6) δ ppm 2.53 (br.s., 1H), 9.63 (s, 1H), 8.82 (d, J = 2.1Hz, 1H), 8 .71 (d, J = 8.8 Hz, 1H), 8.64 (d, J = 8.2 Hz, 1H), 8.55 (d, J = 1.5 Hz, 1H), 8.21 (dd, J = 8.7, 2.2 Hz, 1H), 8.16 (d, J = 9.4 Hz, 1H), 7.93 (dd, J = 8.5, 1.8 Hz, 1H), 3.93. (S, 3H), 3.64 (dd, J = 9.2, 5.7 Hz, 1H), 1.88-2.06 (m, 1H), 0.85 (d, J = 6.7 Hz, 3H) and 0.82 (d, J = 6.7 Hz, 3H); MS (ES +) 489.13.

Example 123: (S) -1- (7- (N- (1-carboxy-2-methylpropyl) sulfamoyl) dibenzo [b, d] thiophen-3-yl) -1H-1,2,3-triazole Preparation of -4-carboxylic acid (S) -1- (7- (N- (1-carboxy-2-methylpropyl) sulfamoyl) dibenzo [b, d] thiophen-3-yl) -1H-1,2, 3-Triazole-4-carboxylic acid was isolated as a by-product in Example 122. MS (ES +) 475.12.

Example 124: (S) -2- (7- (4-cyano-1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid According to a procedure similar to that described in Example 115, using propionitrile, (S) -2- (7- (4-cyano-1H-1,2,3-triazole-1- I) Dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.53 (br.s., 1H), 9.85 (s, 1H), 8.78 (d, J = 2.1 Hz, 1H), 8 .75 (d, J = 8.5 Hz, 1H), 8.65 (d, J = 8.5 Hz, 1H), 8.57 (d, J = 1.2 Hz, 1H), 8.16 (br. s., 1H), 8.13 (dd, J = 8.5, 2.1 Hz, 1H), 7.94 (dd, J = 8.2, 1.8 Hz, 1H), 3.64 (dd, J = 8.7, 5.4 Hz, 1H), 1.87-2.06 (m, 1H), 0.85 (d, J = 7.0 Hz, 3H) and 0.81 (d, J = 7 .0Hz, 3H); MS (ES +) 456.007.

Example 125: (S) -2- (7- (4-Isopropyl-1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid Following the procedure similar to that described in Example 115 and using propionitrile, (S) -2- (7- (4-isopropyl-1H-1,2,3-triazole-1- I) Dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.52 (br.s., 1H), 8.46-8.79 (m, 5H), 8.02-8.26 (m, 2H) 7.92 (dd, J = 8.5, 1.5 Hz, 1H), 3.63 (dd, J = 9.2, 5.7 Hz, 1H), 2.97-3.19 (m, 1H) ), 1.82-2.08 (m, 1H), 1.34 (d, J = 7.0 Hz, 6H), 0.85 (d, J = 6.7 Hz, 3H) and 0.82 (d , J = 6.7 Hz, 3H); MS (ES +) 473.02.

Example 126: (S) -2- (7- (4-carbamoyl-1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid Following the procedure similar to that described in Example 115 and using propioluamide, (S) -2- (7- (4-carbamoyl-1H-1,2,3-triazole-1- I) Dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.52 (br.s., 1H), 9.37 (s, 1H), 8.79 (d, J = 2.1 Hz, 1H), 8 .70 (d, J = 8.8 Hz, 1H), 8.63 (d, J = 8.5 Hz, 1H), 8.55 (d, J = 1.2 Hz, 1H), 8.19 (dd, J = 8.5, 1.8 Hz, 1H), 8.15 (d, J = 9.4 Hz, 1H), 7.98-8.07 (m, 1H), 7.93 (dd, J = 8 .5, 1.5 Hz, 1H), 7.62 (br.s., 1H), 3.64 (dd, J = 9.5, 5.7 Hz, 1H), 1.85-2.06 (m) , 1H), 0.85 (d, J = 6.7 Hz, 3H) and 0.82 (d, J = 6.7 Hz, 3H); MS (ES +) 474.00.

Example 127: (S) -2- (7- (4- (furan-2-yl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamide ) -3-Methylbutanoic acid preparation Following a procedure similar to that described in Example 115, using 2-ethynylfuran, (S) -2- (7- (4- (furan-2-yl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was prepared. MS (ES +) 497.07.

Example 128: Preparation of (R) -2- (7- (4H-1,2,4-triazol-4-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid Step 1 Preparation of (R) -methyl 3-methyl-2- (7-nitrodibenzo [b, d] furan-2-sulfonamido) butanoate 7-nitrodibenzo [b, d] furan-2-sulfonyl chloride (Examples) 1, step 3,570mg, 1.83mmol) and (R) - after methyl 2-amino-3-methylbutanoate hydrochloride (2.0 mmol) was mixed with _CH 2 Cl ₂ in 5 mL, 0 ° C. N- , N-diisopropylethylamine (520 mg, 4 mmol) was added slowly. The mixture was warmed to room temperature over 4 hours and purified by silica gel column chromatography to give (R) -methyl 3-methyl-2- (7-nitrodibenzo [b, d] furan-2-sulfonamido) butanoate as a white solid As a yield of 80%.

Step 2: Preparation of (R) -methyl 2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate (R) -methyl 3-methyl obtained in step 1 2- (7-Nitrodibenzo [b, d] furan-2-sulfonamido) butanoate (820 mg) was mixed with 20 mL MeOH and 100 mg palladium on carbon (Pd / C) (10%). The reaction was performed in a Parr shaker at room temperature overnight under hydrogen (50 psi). (R) -Methyl 2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate by filtering the reaction mixture through Celite® and removing MeOH. (790 mg) was obtained as an off-white solid in quantitative yield.

Step 3: Preparation of (R) -methyl 2- (7- (4H-1,2,4-triazol-4-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate (R) -Methyl 2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate (100 mg, 0.25 mmol) and N, N-dimethyl obtained from step 2 Formamide azine hydrochloride (55 mg, 0.25 mmol) was mixed with toluene (5 mL) and heated to reflux for 24 hours. Toluene was removed under reduced pressure and the residue was purified by HPLC to give (R) -methyl 2- (7- (4H-1,2,4-triazol-4-yl) dibenzo [b, d] furan- 2-sulfonamido) -3-methylbutanoate was obtained as a pale yellow solid.

Step 4: Preparation of (R) -2- (7- (4H-1,2,4-triazol-4-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid From Step 3 The obtained (R) -methyl 2- (7- (4H-1,2,4-triazol-4-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate was converted into methanol. / Dissolved in water (1: 1), and lithium hydroxide (3.0 equivalents) was added thereto. The resulting mixture was stirred at room temperature for 16 hours, diluted with water, acidified to pH ˜3 with 1N HCl and filtered to give the crude product, which was purified by HPLC ( R) -2- (7- (4H-1,2,4-triazol-4-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid (20 mg) as an off-white solid Obtained. ¹ H NMR (400 MHz, MeOD) δ ppm 9.35 (s, 2H), 8.84 (d, J = 1.77 Hz, 1H), 8.53 (d, J = 8.34 Hz, 1H), 8 .23-8.29 (m, 2H), 8.00 (d, J = 8.84 Hz, 1H), 7.95 (dd, J = 8.34, 2.02 Hz, 1H), 3.94 ( dd, 1H), 2.21-2.35 (m, 1H) and 1.18 (dd, 6H); MS (LCMS-ESI, M + H) 414.96.

Example 129: Preparation of (R) -3-methyl-2- (7- (2-oxooxazolidin-3-yl) dibenzo [b, d] furan-2-sulfonamido) butanoic acid Step 1: (R) Preparation of methyl 2- (7-((2-bromoethoxy) carbonylamino) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate In a round bottom flask, (R) -methyl 2 -(7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate (Example 128, Step 2, 156 mg), dichloromethane (5 mL), 2-bromoethylcarbonochloridate ( 1.2 equivalents) and DMAP (2.0 equivalents) were added. The reaction mixture was stirred at room temperature for 2 hours, diluted with water and acidified with 1N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers are washed with 0.5N hydrochloric acid and brine, dried over sodium sulfate, and concentrated to give (R) -methyl 2- (7-((2-bromoethoxy) carbonylamino) dibenzo [b , D] furan-2-sulfonamido) -3-methylbutanoate (198 mg) was obtained as a white solid.

Step 2: Preparation of (R) -methyl 3-methyl-2- (7- (2-oxooxazolidin-3-yl) dibenzo [b, d] furan-2-sulfonamido) butanoate obtained from step 1 ( R) -Methyl 2- (7-((2-bromoethoxy) carbonylamino) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate (198 mg) was dissolved in DMF (2 mL). . Cesium carbonate (2.0 eq) was added and the reaction mixture was heated to 60 ° C. for 4 hours, cooled to room temperature and diluted with water. The precipitate was filtered to give (R) -methyl 3-methyl-2- (7- (2-oxooxazolidin-3-yl) dibenzo [b, d] furan-2-sulfonamido) butanoate (165 mg). Obtained as a white solid.

Step 3: Preparation of (R) -3-methyl-2- (7- (2-oxooxazolidin-3-yl) dibenzo [b, d] furan-2-sulfonamido) butanoic acid obtained from Step 2 ( R) -Methyl 3-methyl-2- (7- (2-oxooxazolidin-3-yl) dibenzo [b, d] furan-2-sulfonamido) butanoate (165 mg) was dissolved in THF (2 mL). To the solution was added water (2 mL) and lithium hydroxide (3.0 eq). The mixture is stirred overnight at room temperature, diluted with water, acidified to pH ˜4 with 2N hydrochloric acid and filtered to give the crude product, which is purified by HPLC to give (R) − 3-Methyl-2- (7- (2-oxooxazolidin-3-yl) dibenzo [b, d] furan-2-sulfonamido) butanoic acid (143 mg) was obtained as an off-white solid. ¹ H NMR (400 MHz, MeOD) δ ppm 8.72 (d, J = 1.52 Hz, 1H), 8.33 (d, J = 8.59 Hz, 1H), 8.25 (d, J = 1. 77 Hz, 1H), 8.17 (dd, J = 8.59, 2.02 Hz, 1H), 7.91 (d, J = 8.59 Hz, 1H), 7.84 (dd, J = 8.59 , 2.02 Hz, 1H), 4.77 (dd, 2H), 4.45 (dd, 2H), 3.87 (d, 1H), 2.20-2.32 (m, 1H) and 1. 16 (dd, 6H); MS (LCMS-ESI, M + H) 433.21.

Example 130: Preparation of (S, E) -2- (8-((dimethylamino) methyleneamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid (S, E) -2 -(8-((Dimethylamino) methyleneamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid is obtained as a by-product from the last step of the scaled up preparation of Example 99. It was. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.67 (s, 1H), 8.30 (d, J = 8.34 Hz, 1H), 8.22 (d, J = 2.53 Hz, 1H ), 8.11-8.17 (m, 1H), 7.85-7.93 (m, 2H), 7.64 (dd, J = 8.84, 2.53 Hz, 1H), 3.61 (T, J = 6.06 Hz, 1H), 3.40 (s, 3H), 3.26 (s, 3H), 1.87-2.07 (m, 1H) and 0.82 (dd, J = 15.41, 6.82 Hz, 6H); MS (LCMS-ESI, M + H) 417.91.

Example 131: Preparation of (S) -2- (8-((3-chloropropoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid described in Example 28. (S) -2- (8-((3-Chloropropoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3 using chloropropyl chloroformate according to a procedure similar to that -Methylbutanoic acid was obtained as a white solid. _{HRMS [C 21 H 23 ClN 2} O 7 S + H] + calcd 483.09873 for; found ^{(ESI-FTMS, [M +} H] 1+) 483.10066.

Example 132: Preparation of (R) -2- (7- (2,5-dimethyl-1H-pyrrol-1-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid Step 1 Preparation of (R) -methyl 2- (7- (2,5-dimethyl-1H-pyrrol-1-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate (R ) -Methyl 2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate (Example 128, Step 2, 200 mg, 0.83 mmol), hexane-2,5- Dione (61 mg, 0.53 mmol) and 4-methylbenzenesulfonic acid (10 mg) were mixed with 3 mL of methanol. (R) -methyl 2- (7- (2,5-dimethyl-1H-pyrrole-1) was irradiated by microwave irradiation at 120 ° C. for 30 minutes, the mixture was concentrated and purified by column chromatography. -Yl) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate was obtained as a white solid in 35% yield.

Step 2: Preparation of (R) -2- (7- (2,5-dimethyl-1H-pyrrol-1-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid From Step 1 The resulting 2- (7- (2,5-dimethyl-1H-pyrrol-1-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate (84 mg) was added to 2 mL of THF. After dissolving in / H ₂ O (1: 1), LiOH (200 mg) was added. The resulting suspension was stirred at room temperature for 3 days and the crude product was purified to give (R) -2- (7- (2,5-dimethyl-1H-pyrrol-1-yl) dibenzo [b , D] furan-2-sulfonamido) -3-methylbutanoic acid (78 mg) was obtained as a pale yellow solid in 97% yield. ¹ H NMR (400 MHz, MeOD) δ ppm 1.14 (d, J = 6.82 Hz, 3H), 1.20 (d, J = 6.82 Hz, 3H), 3.94-3.98 (m, 7H), 6.07 (s, 2H), 7.50 (dd, J = 8.21, 1.64 Hz, 1H), 7.76 (d, J = 1.52 Hz, 1H), 7.98 ( d, J = 8.84 Hz, 1H), 8.25 (dd, J = 8.84, 2.02 Hz, 1H), 8.42-8.47 (m, 1H) and 8.84 (d, J _{= 2.02Hz, 1H); HRMS [} C 23 H 24 N 2 O 5 S + H] + calcd 441.14787 for; found ^{(ESI-FTMS, [M +} H] +) 441.14757.

Example 133: Preparation of (R) -2- (8-bromo-7- (methoxycarbonylamino) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid Step 1: 8-Bromo-7 -Preparation of Nitrodibenzo [b, d] furan-2-sulfonyl chloride To a round bottom flask was added dibenzofuran (15 g) and acetic acid (90 mL). Bromine (6.1 mL) was added via a dropping funnel and the mixture was heated at 55 ° C. overnight. After cooling the reaction mixture to 0 ° C., the precipitate was filtered and air-dried to give 2-bromodibenzofuran (11.3 g).

  2-Bromodibenzofuran (11.3 g) was suspended in dichloromethane (100 mL), and chlorosulfonic acid (4.0 mL, 1.2 eq) was slowly added thereto. The mixture was stirred at room temperature for 4 hours and the resulting precipitate was collected by filtration. The solid was added to thionyl chloride (70 mL) followed by DMF (2 drops). The resulting mixture was stirred at 80 ° C. overnight, concentrated, the solid filtered and washed with ice water to give 8-bromodibenzo [b, d] furan-2-sulfonyl chloride (4. 23g).

  8-Bromodibenzo [b, d] furan-2-sulfonyl chloride (1.0 g) was dissolved in TFA (25 mL), fuming nitric acid (355 μL in 5 mL TFA) was added, and the resulting mixture was stirred at room temperature. Stir overnight. The resulting precipitate was filtered to obtain 8-bromo-7-nitrodibenzo [b, d] furan-2-sulfonyl chloride (0.65 g).

Step 2: Preparation of (R) -methyl 2- (7-amino-8-bromodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate 8-Bromo- obtained from step 1 7-nitrodibenzo [b, d] furan-2-sulfonyl chloride (1.0 g) was dissolved in dichloromethane (10 mL). D-valine methyl ester hydrochloride (1.1 eq) and Hunig's base (N, N-diisopropylethylamine, 2.5 eq) were added. The reaction mixture was stirred at room temperature overnight and extracted with ethyl acetate. The combined organic layers were washed with saturated ammonium chloride solution and brine, dried over sodium sulfate, and concentrated to give the corresponding sulfonamide product (1.19 g).

  The sulfonamide product (1.19 g) was dissolved in ethyl acetate (8 mL) and to this was added tin (II) chloride (2.3 g, 10 eq). The mixture was stirred at 50 ° C. overnight and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over sodium sulfate, and concentrated to give (R) -methyl 2- (7-amino-8-bromodibenzo [b, d] furan-2-sulfonamide). -3-Methylbutanoate was obtained (0.8 g).

Step 3: Preparation of (R) -methyl 2- (8-bromo-7- (methoxycarbonylamino) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate (R) -methyl 2 - (7-amino-8-bromo-dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate (200 mg, 0.44 mmol) and DMAP (65 mg, 0.53 mmol) and _CH 2 Cl ₂ Dissolve in (2 mL) and add methyl chloroformate (50 mg, 0.53 mmol). The mixture was stirred at room temperature overnight and concentrated. The residue was purified by column chromatography purification to give (R) -methyl 2- (8-bromo-7- (methoxycarbonylamino) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate Was obtained as a white solid in 39% yield.

Step 4: Preparation of (R) -2- (8-bromo-7- (methoxycarbonylamino) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid 2- (8-bromo-7- (Methoxycarbonylamino) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate (88 mg) was dissolved in a 1: 1 mixture (2 mL) of hydrochloric acid and acetic acid. The mixture was heated at 115 ° C. for 4 hours. By preparative HPLC purification, (R) -2- (8-bromo-7- (methoxycarbonylamino) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid (36.8 mg) was pale yellow. Obtained as a solid in 43% yield. ¹ H NMR (400 MHz, MeOD) δ ppm 1.13 (d, J = 6.82 Hz, 3H), 1.20 (d, J = 6.82 Hz, 3H), 2.25-2.33 (m, 1H), 3.97 (d, J = 5.56 Hz, 1H), 4.04 (s, 3H), 7.89 (dd, J = 8.84, 0.51 Hz, 1H), 8.18 ( dd, J = 8.72, 1.89 Hz, 1H), 8.38 (s, 1H), 8.46 (s, 1H) and 8.69 (dd, J = 2.02, 0.51 Hz, 1H) _{); HRMS [C 19 H 19} BrN 2 O 7 S + H] + calcd 499.01691 for; found ^{(ESI-FTMS, [M +} H] 1+) 499.01655.

Example 134: Preparation of (S) -2- (8-bromo-7- (methoxycarbonylamino) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid Step 1: (S) -Methyl Preparation of 2- (7-amino-8-bromodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate 8-Bromo-7-nitrodibenzo [b, d] furan-2-sulfonyl Chloride (Example 133, Step 1, 500 mg) was dissolved in dichloromethane (5 mL) and L-valine methyl ester hydrochloride (1.1 eq) and Hunig's base (2.5 eq) were added. The reaction mixture was stirred at room temperature overnight and extracted with ethyl acetate. The combined organic layers were washed with saturated ammonium chloride solution and brine, dried over sodium sulfate, and concentrated to give the corresponding sulfonamide product (690 mg).

  The sulfonamide product (690 mg) was dissolved in ethyl acetate (8 mL) and tin (II) chloride (1.12 g, 10 eq) was added. The mixture was stirred at 50 ° C. overnight and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over sodium sulfate, and concentrated to give (S) -methyl 2- (7-amino-8-bromodibenzo [b, d] furan-2-sulfonamide). -3-Methylbutanoate was obtained (350 mg).

Step 2: Preparation of (S) -methyl 2- (8-bromo-7- (methoxycarbonylamino) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate obtained from step 1 (S) -Methyl 2- (7-amino-8-bromodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate (200 mg, 0.44 mmol) and DMAP (65 mg, 0.53 mmol) ) Was dissolved in CH ₂ Cl ₂ (2 mL) and methyl chloroformate (50 mg, 0.53 mmol) was added. The mixture was stirred at room temperature overnight and concentrated. The residue was purified by column chromatography to give (S) -methyl 2- (8-bromo-7- (methoxycarbonylamino) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate. Obtained in 45% yield as a white solid.

Step 2: Preparation of (S) -2- (8-bromo-7- (methoxycarbonylamino) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid (S) -methyl 2- (8 -Bromo-7- (methoxycarbonylamino) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate (78 mg) was dissolved in a 1: 1 mixture of hydrochloric acid and acetic acid (2 mL) and the mixture Was heated at 115 ° C. for 4 hours. Preparative HPLC purification gave (S) -2- (8-bromo-7- (methoxycarbonylamino) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid (30 mg) as a pale yellow solid. Obtained. ¹ H NMR (400 MHz, MeOD) δ ppm 1.14 (d, J = 6.82 Hz, 3H), 1.21 (d, J = 6.82 Hz, 3H), 2.24-2.34 (m, 1H), 3.98 (d, J = 5.56 Hz, 1H), 4.04 (s, 3H), 7.86-7.90 (m, 1H), 8.18 (dd, J = 8. 59, 2.02 Hz, 1H), 8.36 (s, 1H), 8.43 (s, 1H) and 8.68 (dd, J = 2.02, 0.51 Hz, 1H); calculation for HRMS values _{[C 19 H 19 BrN 2 O} 7 S + H] +499.01691; Found ^{(ESI-FTMS, [M +} H] +) 499.01737.

Example 135: Preparation of (R) -3-methyl-2- (7- (4- (trifluoromethyl) thiazol-2-ylamino) dibenzo [b, d] furan-2-sulfonamido) butanoic acid Step 1 Preparation of (R) -methyl 2- (7-iododibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate (R) -methyl 2- (7-aminodibenzo [b, d ] Furan-2-sulfonamido) -3-methylbutanoate (Example 128, Step 2, 2165 mg, 5.75 mmol) was mixed with hydrochloric acid (18%, 12 mL). The solution was cooled to 0 ° C. and an aqueous solution of sodium nitrite (1.0 M, 9 mL) was added slowly. The reaction mixture was stirred for 20 minutes and a solution of sodium iodide (948 mg, 6.32 mmol) in 3 mL of water was added slowly. The resulting mixture is stirred for 20 minutes, diluted with water and filtered to give (R) -methyl 2- (7-iododibenzo [b, d] furan-2-sulfonamido) -3-methylbutane. Noate was obtained as a dark brown solid in 71% yield.

Step 2: Preparation of (R) -methyl 3-methyl-2- (7- (4- (trifluoromethyl) thiazol-2-ylamino) dibenzo [b, d] furan-2-sulfonamido) butanoate From step 1 Obtained (R) -methyl 2- (7-iododibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate (145 mg, 0.3 mmol), 3- (trifluoromethyl) pyrazole (121 mg, 0.9 mmol), trans-N, N′-dimethyl-1,2-cyclohexanediamine (8.5 mg, 0.2 mmol), CuI (3 mg, 0.05 mmol) and K ₃ PO ₄ (133 mg, 2 0.1 mmol) was mixed in 2 mL of toluene. 35 mg (R) -methyl 3-methyl-2- (7- (4- (trifluoromethyl) thiazole) was obtained by irradiating the mixture with microwaves at 130 ° C. for 3 hours and purifying the mixture by preparative HPLC. 2-ylamino) dibenzo [b, d] furan-2-sulfonamido) butanoate was obtained in 22% yield.

Step 3: Preparation of (R) -3-methyl-2- (7- (4- (trifluoromethyl) thiazol-2-ylamino) dibenzo [b, d] furan-2-sulfonamido) butanoic acid From Step 2 The resulting (R) -methyl 3-methyl-2- (7- (4- (trifluoromethyl) thiazol-2-ylamino) dibenzo [b, d] furan-2-sulfonamido) butanoate (35 mg, 0. 06 mmol) was dissolved in THF / MeOH / water (1: 1: 1, 2 mL) and 5 equivalents of lithium hydroxide was added. The reaction mixture is stirred overnight, diluted with water, acidified to pH 4-5, and filtered to give (R) -3-methyl-2- (7- (4- (trifluoromethyl) thiazole-2 -Ilamino) dibenzo [b, d] furan-2-sulfonamido) butanoic acid was obtained as a white solid in 46% yield. ¹ H NMR (400 MHz, MeOD) δ ppm 0.91 (d, J = 6.82 Hz, 3H), 0.98 (d, J = 6.82 Hz, 3H), 2.00-2.11 (m, 1H), 3.71 (d, J = 5.31 Hz, 1H), 7.35 (s, 1H), 7.42 (dd, J = 8.46, 1.39 Hz, 2H), 7.66 ( d, J = 8.84 Hz, 2H), 7.91 (dd, J = 8.72, 1.39 Hz, 2H), 7.96-8.01 (m, 1H), 8.29-8.32. (m, J = 1.26Hz, 1H ) and _{8.42-8.45 (m, 1H); HRMS} [C 21 H 18 F 3 N 3 O 5 S 2 + H] + calculated for 514.07127; Found (ESI-FTMS, [M + H] ¹⁺ ) 514.007107.

Example 136: (S) -3-Methyl-2- (8- (3- (4-nitrophenyl) -1H-pyrazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid Following a procedure similar to that described in Example 135, using 3- (4-nitrophenyl) -1H-pyrazole, (S) -3-methyl-2- (8- (3- ( 4-Nitrophenyl) -1H-pyrazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid was obtained as a white solid. ¹ H NMR (400 MHz, MeOD) δ ppm 0.92 (d, J = 2.78 Hz, 3H), 0.94 (d, J = 2.78 Hz, 3H), 1.99-2.06 (m, 1H), 3.76 (d, J = 6.32 Hz, 1H), 7.09 (d, J = 2.78 Hz, 1H), 7.81 (d, J = 0.51 Hz, 1H), 7. 83 (s, 1H), 7.89 (dd, J = 8.21, 1.64 Hz, 1H), 8.10-8.15 (m, 2H), 8.18-8.22 (m, 2H) ), 8.29 (dd, J = 8.08, 0.51 Hz, 1H), 8.31-8.35 (m, 2H), 8.41 (d, J = 2.53 Hz, 1H) and 8 .61-8.63 (m, 1H).

Example 137: Preparation of (R) -2- (7- (1H-pyrrol-1-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid Step 1: (R) -Methyl Preparation of 2- (7- (1H-pyrrol-1-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate (S) -Methyl 2- (7-amino-8- Bromodibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate (Example 134, Step 1, 100 mg, 0.27 mmol) and 2,5-dimethoxytetrahydrofuran (43 mg, 0.33 mmol). Mixed with 2 mL AcOH. The mixture is stirred at 70 ° C. for 1 hour, concentrated and purified by preparative HPLC to give (R) -methyl 2- (7- (1H-pyrrol-1-yl) dibenzo [b, d] furan- 2-sulfonamido) -3-methylbutanoate was obtained as a white solid in 43% yield.

Step 2: Preparation of (R) -2- (7- (1H-pyrrol-1-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid (R) -methyl 2- (7 -(1H-pyrrol-1-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoate (43 mg) was dissolved in 2 mL THF and aqueous LiOH (200 mg in 2 mL water). And the resulting suspension was stirred at room temperature for 3 days. By acidic aqueous workup, (R) -2- (7- (1H-pyrrol-1-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid (28. 4 mg) was obtained as a pale yellow solid in 68% yield. ¹ H NMR (400 MHz, MeOD) δ ppm 0.92 (d, J = 6.82 Hz, 3H), 0.98 (d, J = 6.82 Hz, 3H), 2.01-2.09 (m, 1H), 3.73 (d, J = 5.81 Hz, 1H), 6.33-6.36 (m, 2H), 7.29-7.31 (m, 2H), 7.59 (dd, J = 8.46, 1.89 Hz, 1H), 7.71 (dd, J = 8.84, 0.51 Hz, 1H), 7.78 (d, J = 1.52 Hz, 1H), 7.98 (Dd, J = 8.72, 1.89 Hz, 1H), 8.15 (d, J = 8.34 Hz, 1H) and 8.53 (dd, J = 1.89, 0.63 Hz, 1H); _{HRMS: [C 21 H 20 N} 2 O 5 S + H] + calcd 413.11657 for; found (ESI-FTMS, [ + ^H] 1+) 413.11639.

Example 138: Preparation of (S) -2- (7-aminodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Step 1: 8-bromodibenzo [b, d] furan-3- Preparation of sulfonyl chloride Dibenzo [b, d] furan-3-sulfonyl chloride (Example 28, Step 2, 5.3 g, 20 mmol) was mixed with AcOH (glacial acetic acid, 120 mL) and bromine (10 mL, 10 eq). The mixture was stirred at 70 ° C. for 4 hours to remove excess bromine and then filtered to obtain 5.4 g of 8-bromodibenzo [b, d] furan-3-sulfonyl chloride as a light brown solid. .

Step 2: Preparation of (S) -methyl 2- (8-bromodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate 8-bromodibenzo [b, d] furan-3-sulfonyl Chloride (3.46 g, 10 mmol) and (S) -methyl 2-amino-3-methylbutanoate hydrochloride (1.1 eq) were mixed with CH ₂ Cl ₂ (30 mL) and N, N-diisopropylethylamine. (3.84 mL, 2.2 eq) was added. The mixture was stirred at room temperature for 5 hours and purified by column chromatography to give (S) -methyl 2- (8-bromodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (4 0.7 g) was obtained as a white solid.

Step 3: Preparation of (S) -methyl 2- (8-bromo-7-nitrodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate 2- (8-bromodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (3.14 g, 7.1 mmol) and HNO ₃ (1.0 g, 14.2 mmol, 90%) were added to TFA (6 mL) and CH ₂ Cl _2. (1 mL). The mixture was stirred at room temperature for 5 hours, concentrated and purified by silica gel column chromatography to give (S) -methyl 2- (8-bromo-7-nitrodibenzo [b, d] furan-3-sulfonamide). -3-Methylbutanoate was obtained as a white solid in 71% yield.

Step 4: Preparation of (S) -methyl 2- (7-aminodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (S) -Methyl 2- (8-bromo-7- Nitrodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (11.56 g, 23.8 mmol) was mixed with 200 mL MeOH and 700 mg Pd / C. The reaction was performed in a Parr shaker at room temperature overnight under H ₂ (50 psi). The reaction mixture was filtered through celite and the filtrate was concentrated to give 8.92 g of (S) -methyl 2- (7-aminodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate. Was obtained as a gray solid.

Step 5: Preparation of (S) -2- (7-aminodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid (S) -methyl 2- (7-aminodibenzo [b, d] Furan-3-sulfonamido) -3-methylbutanoate (87 mg) was dissolved in 2 mL of THF and LiOH solution (1 mL, 0.9 M in MeOH / H ₂ O (1: 1)) was added. The resulting suspension was stirred at room temperature for 4 days and THF was removed under reduced pressure. The residual aqueous solution was acidified to pH˜1 and filtered to give (S) -2- (7-aminodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid as a pale yellow solid. % Yield. _{HRMS: [C 17 H 18 N} 2 O 5 S + H] + calcd 363.10092 for; found ^{(ESI-FTMS, [M +} H] 1+) 363.10145.

Example 139: Preparation of (S) -2- (7- (1H-pyrrol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Step 1: (S) -Methyl Preparation of 2- (7- (1H-pyrrol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (S) -Methyl 2- (7-aminodibenzo [b , D] furan-3-sulfonamido) -3-methylbutanoate (Example 138, Step 4, 139 mg, 0.37 mmol) and 2,5-dimethoxytetrahydrofuran (74 mg, 0.3 mmol) in AcOH (2 mL). Mixed with. The mixture is stirred at 70 ° C. for 1 hour, concentrated and purified by preparative HPLC to give (S) -methyl 2- (7- (1H-pyrrol-1-yl) dibenzo [b, d] furan- 3-sulfonamido) -3-methylbutanoate was obtained as a white solid in 54% yield.

Step 2: Preparation of (S) -2- (7- (1H-pyrrol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid (S) -methyl 2- (7 -(1H-pyrrol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (85 mg) was dissolved in 2 mL of THF and LiOH solution (1 mL, 0.9 M, In MeOH / H ₂ O (1: 1). The resulting suspension was stirred at room temperature for 4 days and THF was removed under reduced pressure. The residual aqueous solution was acidified to pH˜1 and filtered to give (S) -2- (7- (1H-pyrrol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3- Methylbutanoic acid was obtained as a pale yellow solid in 97% yield. MS (LC-ESIMS) 413.2.

Example 140: Preparation of (S) -2- (7- (2,5-dimethyl-1H-pyrrol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Step 1 Preparation of (S) -methyl 2- (7- (2,5-dimethyl-1H-pyrrol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate ) -Methyl 2- (7-aminodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (Example 138, Step 4, 310 mg, 0.83 mmol), Acetonylacetone (943 mg, 8.3 mmol) and bismuth (III) nitrate pentahydrate (62 mg) were mixed with 20 mL of CH ₂ Cl ₂ . The mixture was stirred at room temperature for 20 hours, concentrated and purified by column chromatography to give (S) -methyl 2- (7- (2,5-dimethyl-1H-pyrrol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate was obtained as a white solid in 35% yield.

Step 2: Preparation of (S) -2- (7- (2,5-dimethyl-1H-pyrrol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid (S) -Methyl 2- (7- (2,5-dimethyl-1H-pyrrol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (91 mg) in 2 mL THF Upon dissolution, LiOH solution (1 mL, 0.9 M in MeOH / H ₂ O (1: 1)) was added. The resulting suspension was stirred at room temperature for 3 days and THF was removed under reduced pressure. The remaining aqueous solution was acidified to pH˜1 and filtered to give (S) -2- (7- (2,5-dimethyl-1H-pyrrol-1-yl) dibenzo [b, d] furan-3- Sulfonamido) -3-methylbutanoic acid was obtained as a white solid in 97% yield. _{HRMS: [C 23 H 24 N} 2 O 5 S + H] + calcd 441.14787 for; found ^{(ESI-FTMS, [M +} H] 1+) 441.14906.

Example 141: Preparation of (S) -3-methyl-2- (7- (2-oxooxazolidin-3-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid Step 1: (S) Preparation of methyl 2- (7-((2-bromoethoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (S) -Methyl 2- (7-amino Dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (Example 138, Step 4, 226 mg, 0.6 mmol) and DMAP (100 mg, 0.72 mmol) in 5 mL of CH ₂ Cl ₂ After being dissolved in methyl chloroformate (169 mg, 0.9 mmol) was added. The mixture was stirred overnight at room temperature, concentrated and purified by column chromatography to give (S) -methyl 2- (7-((2-bromoethoxy) carbonylamino) dibenzo [b, d] furan-3. -Sulfonamido) -3-methylbutanoate was obtained as a white solid in 91% yield.

Step 2: Preparation of (S) -methyl 3-methyl-2- (7- (2-oxooxazolidin-3-yl) dibenzo [b, d] furan-3-sulfonamido) butanoate (S) in 6 mL DMF ) -Methyl 2- (7-((2-bromoethoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (270 mg) in a solution of 160 mg K ₂ CO ₃ was added. The mixture is stirred at room temperature for 6 hours and purified by preparative HPLC to give (S) -methyl 3-methyl-2- (7- (2-oxooxazolidin-3-yl) dibenzo [b, d] furan. -3-Sulfonamido) butanoate was obtained as a white solid in 50% yield.

Step 3: Preparation of (S) -3-methyl-2- (7- (2-oxooxazolidin-3-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid (S) -methyl 3- Methyl-2- (7- (2-oxooxazolidin-3-yl) dibenzo [b, d] furan-3-sulfonamido) butanoate (109 mg) was added to 5 mL AcOH, 4 mL 37% HCl and 1 mL H _2. Mixed with a solution of O. The mixture is stirred at 60 ° C. for 20 hours and purified by preparative HPLC to give (S) -3-methyl-2- (7- (2-oxooxazolidin-3-yl) dibenzo [b, d] furan. -3-Sulfonamido) butanoic acid was obtained as a white solid in 40% yield. _{HRMS: [C 20 H 20 N} 2 O 7 S + H] + calcd 433.10640 for; found ^{(ESI-FTMS, [M +} H] 1+) 433.10635.

Example 142 Preparation of (S) -2- (7- (2-Chloroethylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid This compound was prepared according to Step 3 of Example 141. Isolated as an off-white solid in 10% yield. _{HRMS: [C 19 H 21 ClN} 2 O 5 S + H] + calcd 425.09325 for; found ^{(ESI-FTMS, [M +} H] 1+) 425.09269.

Example 143: Preparation of (S) -2- (7- (N- (2-hydroxyethyl) acetamido) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid (S) -2- 7- (N-2-hydroxyethylacetamido) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid as a by-product in Step 3 of Example 141 in 10% yield off-white color Isolated as a solid. _{HRMS: [C 21 H 24 N} 2 O 7 S + H] + calcd 449.13770 for; found ^{(ESI-FTMS, [M +} H] 1+) 449.1384.

Example 144: (S) -3-Methyl-2- (7- (3- (trifluoromethyl) -1H-pyrazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid Preparation Step 1: Preparation of (S) -methyl 2- (7-iododibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (S) -methyl 2- (7 -Aminodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (Example 138, Step 4, 3.72 g, 9.9 mmol), 3.5 mL HCl, 12 mL H _To a mixture of ₂ O and 50 mL AcOH was added NaNO ₂ solution (2M, 7.5 mL) slowly followed by NaI (11.87 g, 80 mmol). The mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was filtered, the solid washed with water and further purified by column chromatography to give 3.94 g of (S) -methyl 2- (7-iododibenzo [b, d] furan-3-sulfonamide. ) -3-Methylbutanoate was obtained as a gray solid.

Step 2: Preparation of (S) -methyl 3-methyl-2- (7- (3- (trifluoromethyl) -1H-pyrazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) butanoate (S) -methyl 2- (7-iododibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (145 mg, 0.3 mmol), 3- (trifluoromethyl) pyrazole (121 mg, 0.9 mmol), trans-N, N′-dimethyl-1,2-cyclohexanediamine (8.5 mg, 0.2 mmol), CuI (3 mg, 0.05 mmol) and K ₃ PO ₄ (133 mg, 2.1 mmol) Was mixed with 2 mL of toluene. By irradiating the mixture with microwave for 3 hours at 130 ° C. and purifying by preparative HPLC, 98 mg of (S) -methyl 3-methyl-2- (7- (3- (trifluoromethyl) -1H -Pyrazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) butanoate was obtained as a white solid in 66% yield.

Step 3: Preparation of (S) -3-methyl-2- (7- (3- (trifluoromethyl) -1H-pyrazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid 2 mL of (S) -methyl 3-methyl-2- (7- (3- (trifluoromethyl) -1H-pyrazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) butanoate (90 mg) Was dissolved in THF and LiOH solution (1 mL, 0.9 M in MeOH / H ₂ O (1: 1)) was added. The resulting suspension was stirred at room temperature for 3 days and THF was removed under reduced pressure. The remaining aqueous solution was acidified to pH˜2 and filtered to give (S) -3-methyl-2- (7- (3- (trifluoromethyl) -1H-pyrazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid was obtained as a white solid in 97% yield. _{HRMS: [C 21 H 18 F} 3 N 3 O 5 S + H] + calcd 482.09920 for; found ^{(ESI-FTMS, [M +} H] 1+) 482.09985.

Example 145: Preparation of (S) -2- (8-bromo-7-nitrodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid (S) -methyl 2- (8-bromo- 7-nitrodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (Example 138, step 3, 187 mg) was dissolved in 4 mL of THF and LiOH solution (1 mL, 0.9 M, In MeOH / H ₂ O (1: 1). The resulting suspension was stirred at room temperature for 4 days and THF was removed under reduced pressure. The residual aqueous solution was acidified to pH ˜1 and filtered to give (S) -2- (8-bromo-7-nitrodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid lightly. Obtained in 70% yield as a yellow solid. _{HRMS: [C 17 H 15 BrN} 2 O 7 S + H] + calcd 470.98561 for; found ^{(ESI-FTMS, [M +} H] 1+) 470.98719.

Example 146: Preparation of (S) -3-methyl-2- (7-nitrodibenzo [b, d] furan-3-sulfonamido) butanoic acid (S) -methyl 3-methyl-2- (7-nitro Dibenzo [b, d] furan-3-sulfonamido) butanoate (byproduct in Step 4 of Example 138, 30 mg) was dissolved in 1 mL THF and LiOH solution (1 mL, 0.9 M, MeOH / H ₂ O (1 1) Medium) was added. The resulting suspension was stirred at room temperature for 4 days and THF was removed under reduced pressure. Acidify the remaining aqueous solution to pH ˜1 and filter to give (S) -3-methyl-2- (7-nitrodibenzo [b, d] furan-3-sulfonamido) butanoic acid as a pale yellow solid. Obtained in 69% yield. _{HRMS: [C 17 H 16 N} 2 O 7 S + H] + calcd 393.07510 for; found ^{(ESI-FTMS, [M +} H] 1+) 393.07643.

Example 147: Preparation of (S) -2- (7-amino-8-bromodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Step 1: (S) -Methyl 2- (7 Preparation of amino-8-bromodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (S) -methyl 2- (8-bromo-7-nitrodibenzo [b, d] furan -3-sulfonamido) -3-methylbutanoate (Example 138, Step 3, 1.75 g, 3.6 mmol) and tin (II) chloride (2.73 mg, 14.4 mmol) mixed with 20 mL EtOAc did. The mixture is stirred at 60 ° C. overnight, concentrated and purified by column chromatography to give (S) -methyl 2- (7-amino-8-bromodibenzo [b, d] furan-3-sulfonamide). -3-Methylbutanoate was obtained as a white solid in 60% yield.

Step 2: Preparation of (S) -2- (7-amino-8-bromodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid (S) -Methyl 2- obtained from Step 1 (7-amino-8-bromodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (45 mg) was dissolved in 1 mL of THF and LiOH solution (1 mL, 0.9 M, MeOH / H ₂ O (1: 1)) was added. The resulting suspension was stirred at room temperature for 4 days and THF was removed under reduced pressure. The remaining aqueous solution was acidified to pH ˜1 and filtered to give (S) -2- (7-amino-8-bromodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid in white. Obtained as a solid in 95% yield. MS (LC-ESIMS, [M + H] < ¹⁺ >) 441.1.

Example 148: Preparation of (R) -3-methyl-2- (7-nitrodibenzo [b, d] furan-3-sulfonamido) butanoic acid Step 1: (R) -Methyl 3-methyl-2- ( Preparation of 7-nitrodibenzo [b, d] furan-3-sulfonamido) butanoate 7-nitrodibenzo [b, d] furan-3-sulfonyl chloride (by-product in step 3 of Example 28, 0.63 g, 2. 02 mmol) and (R) -methyl 2-amino-3-methylbutanoate hydrochloride (346 mg, 1.02 mmol) were mixed with 30 mL of CH ₂ Cl ₂ and N, N-diisopropylethylamine (0.71 mL, 4 .04 mmol) was added. The mixture was stirred at room temperature for 5 hours and purified by column chromatography to give 0.69 g of (R) -methyl 3-methyl-2- (7-nitrodibenzo [b, d] furan-3-sulfonamide). Butanoate was obtained as a white solid in 85% yield.

Step 2: Preparation of (R) -3-methyl-2- (7-nitrodibenzo [b, d] furan-3-sulfonamido) butanoic acid (R) -methyl 3-methyl-2- (7-nitrodibenzo) [B, d] furan-3-sulfonamido) butanoate (114 mg) was dissolved in 4 mL of THF and LiOH solution (1 mL, 0.9 M in MeOH / H ₂ O (1: 1)) was added. The resulting suspension was stirred at room temperature for 4 days and THF was removed under reduced pressure. The remaining aqueous solution was acidified to pH˜1 and filtered to give (R) -3-methyl-2- (7-nitrodibenzo [b, d] furan-3-sulfonamido) butanoic acid as a white solid. % Yield. _{HRMS: [C 17 H 16 N} 2 O 7 S + H] + calcd 393.07510 for; found ^{(ESI-FTMS, [M +} H] 1+) 393.07453.

Example 149: Preparation of (R) -2- (7- (methoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Step 1: (R) -Methyl 2- (7 Preparation of aminodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (R) -methyl 3-methyl-2- (7-nitrodibenzo [b, d] furan-3-sulfone Amido) butanoate (Example 148, Step 1, 405 mg) and 100 mg of Pd / C (10%) were mixed with 50 mL of MeOH. The reaction was performed in a Parr shaker at room temperature overnight under H ₂ (50 psi). The reaction mixture was filtered through celite and the filtrate was concentrated to give 333 mg of (R) -methyl 2- (7-aminodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate as yellow. Obtained in 90% yield as a solid.

Step 2: Preparation of (R) -methyl 2- (7- (methoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (R) -methyl 2- (7- Aminodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (51 mg, 0.13 mol) and DMAP (20 mg, 0.16 mmol) were dissolved in 3 mL of CH ₂ Cl ₂ and chloroformate Methyl (15 mg, 0.16 mmol) was added. The mixture is stirred at room temperature overnight, concentrated and purified by silica gel column chromatography to give (R) -methyl 2- (7- (methoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamide). -3-Methylbutanoate was obtained as a white solid in 71% yield.

Step 3: Preparation of (R) -2- (7- (methoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid (R) -methyl 2- (7- (methoxycarbonyl) Amino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (40 mg) was mixed with 3 mL AcOH and 6 mL 37% HCl. The resulting suspension was stirred at room temperature for 18 hours, concentrated and purified by preparative HPLC to give (R) -2- (7- (methoxycarbonylamino) dibenzo [b, d] furan-3. -Sulfonamido) -3-methylbutanoic acid was obtained as a white solid in 74% yield. _{HRMS: [C 19 H 20 N} 2 O 7 S + H] + calcd 421.10640 for; found ^{(ESI-FTMS, [M +} H] 1+) 421.10674.

Example 150: Preparation of (R) -2- (7- (3- (3,4-difluorophenyl) ureido) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Step 1: ( Preparation of R) -methyl 2- (7- (3- (3,4-difluorophenyl) ureido) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (R) -methyl 2 -(7-aminodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (Example 148, Step 1, 43 mg, 0.11 mmol) and 3-ethylenyl isocyanate ( 21 mg, 0.14 mmol) was mixed with 2 mL of THF. (R) -methyl 2- (7- (3- (3,4-difluorophenyl) ureido) was obtained by irradiating the mixture with microwaves at 120 ° C. for 20 minutes, concentrating and purifying by silica gel column chromatography. Dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate was obtained as a white solid in 72% yield.

Step 2: Preparation of (R) -2- (7- (3- (3,4-difluorophenyl) ureido) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid (R) -methyl 2- (7- (3- (3,4-difluorophenyl) ureido) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (40 mg) was dissolved in 1 mL of THF and LiOH was added. The solution (1 mL, 0.9 M in MeOH / H ₂ O (1: 1)) was added. The resulting suspension was stirred at room temperature for 4 days and THF was removed under reduced pressure. (R) -2- (7- (3- (3,4-difluorophenyl) ureido) dibenzo [b, d] furan-3-sulfonamide is obtained by acidifying the remaining aqueous solution to pH about 1 and filtering. ) -3-Methylbutanoic acid was obtained as a white solid in 95% yield. _{HRMS: [C 24 H 21 F} 2 N 3 O 6 S + H] + calcd 518.11919 for; found ^{(ESI-FTMS, [M +} H] 1+) 518.11967.

Example 151: Preparation of (S) -2- (7- (methoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Step 1: (S) -tert-Butyl 3- Preparation of methyl-2- (7-nitrodibenzo [b, d] furan-3-sulfonamido) butanoate 7-nitrodibenzo [b, d] furan-3-sulfonyl chloride (isolated in Step 3 of Example 28) Side product, 0.63 g, 2.02 mmol) and (S) -tert-butyl 2-amino-3-methylbutanoate hydrochloride (346 mg, 1.02 mmol) were mixed with 30 mL CH ₂ Cl ₂ and N , N-diisopropylethylamine (0.71 mL, 4.04 mmol) was added. The mixture was stirred at room temperature for 5 hours and purified by silica gel column chromatography to give 0.69 g of (S) -tert-butyl 3-methyl-2- (7-nitrodibenzo [b, d] furan-3-sulfone. Amido) butanoate was obtained as a white solid in 85% yield.

Step 2: Preparation of (S) -tert-butyl 2- (7-aminodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (S) -tert-butyl 3-methyl-2 -(7-Nitrodibenzo [b, d] furan-3-sulfonamido) butanoate (420 mg) and 200 mg Pd / C (10%) were mixed with 150 mL MeOH. The reaction was performed in a Parr shaker at room temperature overnight under H ₂ (50 psi). The reaction mixture was filtered through celite and the filtrate was concentrated to give 325 mg of (S) -tert-butyl 2- (7-aminodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate. Was obtained as a yellow solid in 100% yield.

Step 3: Preparation of (S) -tert-butyl 2- (7- (methoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (S) -tert-butyl 2 -(7-aminodibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (370 mg, 0.88 mol) and DMAP (0.13 g, 1.06 mmol) in 14 mL CH ₂ Cl ₂ And methyl chloroformate (100 mg, 1.06 mmol) was added. The mixture is stirred at room temperature overnight, concentrated and purified by silica gel column chromatography to give (S) -tert-butyl 2- (7- (methoxycarbonylamino) dibenzo [b, d] furan-3-sulfone. Amido) -3-methylbutanoate was obtained as a white solid in 93% yield.

Step 4: Preparation of (S) -2- (7- (methoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid (S) -tert-butyl 2- (7- ( Methoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (335 mg) is mixed with 6 mL TFA / CH ₂ Cl ₂ (1: 1) and stirred at room temperature for 4 hours. did. The solvent is removed under reduced pressure and the residue is triturated in MeCN / water followed by a lyophilization process to give (S) -2- (7- (methoxycarbonylamino) dibenzo [b, d] furan-3- Sulfonamido) -3-methylbutanoic acid was obtained as a white solid in 96% yield. _{HRMS: [C 19 H 20 N} 2 O 7 S + H] + calcd 421.10640 for; found ^{(ESI-FTMS, [M +} H] 1+) 421.1064.

Example 152: Preparation of (S) -2- (7-((2-fluoroethoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid described in Example 151 Following a procedure similar to that using 2-fluoroethylcarbonochloridate, (S) -2- (7-((2-fluoroethoxy) carbonylamino) dibenzo [b, d] furan-3-sulfone Amido) -3-methylbutanoic acid was prepared. _{HRMS: [C 20 H 21 FN} 2 O 7 S + H] + calcd 453.11263 for; found ^{(ESI-FTMS, [M +} H] 1+) 453.11285.

Example 153: Preparation of (S) -2- (7-((but-2-ynyloxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid described in Example 151 (S) -2- (7-((but-2-ynyloxy) carbonylamino) dibenzo [b, d] furan using but-2-ynylcarbonochloridate according to a procedure similar to that described above. -3-Sulfonamido) -3-methylbutanoic acid was prepared. _{HRMS: [C 22 H 22 N} 2 O 7 S + H] + calcd 459.12205 for; found ^{(ESI-FTMS, [M +} H] 1+) 459.12354.

Example 154: Preparation of (S) -2- (7-((4-fluorophenoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid described in Example 151 (S) -2- (7-((4-Fluorophenoxy) carbonylamino) dibenzo [b, d] furan-3 using but-2-ynylcarbonochloridate following a procedure similar to that -Sulfonamido) -3-methylbutanoic acid was prepared. _{HRMS: [C 24 H 21 FN} 2 O 7 S + H] + calcd 501.11263 for; found ^{(ESI-FTMS, [M +} H] 1+) 501.11483.

Example 155: Preparation of (S) -3-methyl-2- (7- (3-thiophen-3-ylureido) dibenzo [b, d] furan-3-sulfonamido) butanoic acid Step 1: (S)- Preparation of tert-butyl 3-methyl-2- (7- (3-thiophen-3-ylureido) dibenzo [b, d] furan-3-sulfonamido) butanoate (S) -tert-butyl 2- (7-amino Dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (Example 151, Step 2, 60 mg, 0.14 mmol) and 3-isocyanatothiophene (18 mg, 0.17 mmol) in 2 mL Mixed with THF. (S) -tert-butyl 3-methyl-2- (7- (3-thiophene-) by irradiating the mixture with microwaves at 120 ° C. for 20 minutes, concentrating the mixture and purifying by silica gel column chromatography. 3-ylureido) dibenzo [b, d] furan-3-sulfonamido) butanoate was obtained as a white solid in 38% yield.

Step 2: Preparation of (S) -3-methyl-2- (7- (3-thiophen-3-ylureido) dibenzo [b, d] furan-3-sulfonamido) butanoic acid (S) -tert-butyl 3 - methyl-2- (7- (3-thiophen-3-ylureido) dibenzo [b, d] furan-3-sulfonamido) butanoate (36 mg) and 1mL of _{TFA / CH 2 Cl 2 (1} : 1) and mixed did. The resulting mixture was stirred at room temperature for 4 hours, concentrated under reduced pressure, the residue was triturated in MeCN / water and then subjected to a lyophilization process to give (S) -3-methyl-2- (7- ( 3-thiophen-3-ylureido) dibenzo [b, d] furan-3-sulfonamido) butanoic acid was obtained as a white solid in 90% yield. _{HRMS: [C 22 H 21 N} 3 O 6 S 2 + H] + calcd 488.09445 for; found ^{(ESI-FTMS, [M +} H] 1+) 488.09462.

Example 156: (S) -3-Methyl-2- (7- (3- (2- (thiophen-2-yl) ethyl) ureido) dibenzo [b, d] furan-3-sulfonamido) butanoic acid Preparation Following a procedure analogous to that described in Example 155 and using 2- (2-isocyanatoethyl) thiophene, (S) -3-methyl-2- (7- (3- (2- (2- ( Thiophen-2-yl) ethyl) ureido) dibenzo [b, d] furan-3-sulfonamido) butanoic acid was prepared. _{HRMS: [C 24 H 25 N} 3 O 6 S 2 + H] + calcd 516.12575 for; found ^{(ESI-FTMS, [M +} H] 1+) 516.12506.

Example 157: Preparation of (S) -3-methyl-2- (7-ureidodibenzo [b, d] furan-3-sulfonamido) butanoic acid According to a procedure analogous to that described in Example 155, (S) -3-Methyl-2- (7-ureidodibenzo [b, d] furan-3-sulfonamido) butanoic acid was prepared using-(isocyanatomethyl) -4-methoxybenzene. _{HRMS: [C 18 H 19 N} 3 O 6 S + H] + calcd 406.10673 for; found ^{(ESI-FTMS, [M +} H] 1+) 406.10682.

Example 158: Preparation of (S) -2- (7- (3- (3,4-difluorophenyl) ureido) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Following a procedure similar to that described, using 1,2-difluoro-4-isocyanatobenzene, (S) -2- (7- (3- (3,4-difluorophenyl) ureido) dibenzo [ b, d] furan-3-sulfonamido) -3-methylbutanoic acid was prepared. _{HRMS: [C 24 H 21 F} 2 N 3 O 6 S + H] + calcd 518.11919 for; found ^{(ESI-FTMS, [M +} H] 1+), 518.11942.

Example 159: Preparation of (S) -2- (7- (ethylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Step 1: (S) -Methyl 2- (7- Preparation of (Ethylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (S) -Methyl 2- (8-bromo-7-nitrodibenzo [b, d] furan-3 -Sulfonamido) -3-methylbutanoate (Example 138, step 3, 550 mg) and 1 g Pd / C (10%) were mixed with 150 mL MeOH and 2 mL MeCN. The reaction was performed in a Parr shaker at room temperature overnight under H ₂ (50 psi). The reaction mixture was filtered through Celite® and the filtrate was concentrated to give 330 mg of (S) -methyl 2- (7- (ethylamino) dibenzo [b, d] furan-3-sulfonamide) -3. -Methylbutanoate was obtained as a yellow solid in 72% yield.

Step 2: Preparation of (S) -2- (7- (ethylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid (S) -methyl 2- (7- (ethylamino) Dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (140 mg) was dissolved in 2 mL of THF and LiOH solution (1 mL, 0.9 M, MeOH / H ₂ O (1: 1). Medium) was added. The resulting suspension was stirred at room temperature for 4 days and THF was removed under reduced pressure. The residual aqueous solution was acidified to pH˜1 and filtered to give (S) -2- (7- (ethylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid as a pale yellow color. Obtained as a solid in 95% yield. _{HRMS: [C 19 H 22 N} 2 O 5 S + H] + calcd 391.13222 for; found ^{(ESI-FTMS, [M +} H] 1+) 391.13253.

Example 160: Preparation of (S) -2- (7- (ethyl (methoxycarbonyl) amino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Step 1: (S) -Methyl 2 Preparation of-(7- (ethyl (methoxycarbonyl) amino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (S) -methyl 2- (7- (ethylamino) dibenzo [ b, d] furan-3-sulfonamido) -3-methylbutanoate (example 159, step 1,31Mg, 0.08 mol) and DMAP (12 mg, 0.09 mmol) dissolved in of _CH 2 Cl ₂ 1mL And methyl chloroformate (8.7 mg, 0.09 mmol) was added. The mixture is stirred at room temperature overnight, concentrated and purified by silica gel column chromatography to give (S) -methyl 2- (7- (ethyl (methoxycarbonyl) amino) dibenzo [b, d] furan-3- Sulfonamido) -3-methylbutanoate was obtained as a white solid in 90% yield.

Step 2: Preparation of (S) -2- (7- (ethyl (methoxycarbonyl) amino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid (S) -methyl 2- (7- (Ethyl (methoxycarbonyl) amino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (14 mg) was dissolved in 0.5 mL THF and LiOH solution (1 mL, 0.9 M, In MeOH / H ₂ O (1: 1). The resulting suspension was stirred at room temperature for 3 days and THF was removed under reduced pressure. The residual aqueous solution was acidified to pH˜2 and filtered to give (S) -2- (7- (ethyl (methoxycarbonyl) amino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutane. The acid was obtained as a white solid in 95% yield. _{HRMS: [C 21 H 24 N} 2 O 7 S + H] + calcd 449.13770 for; found ^{(ESI-FTMS, [M +} H] 1+) 449.13776.

Example 161: Preparation of (S) -2- (7- (ethyl (methyl) amino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Step 1: (S) -Methyl 2- Preparation of (7- (ethyl (methyl) amino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate HCHO (32 mg, 37%, 0.4 mmol) and H ₂ SO 4 (5 μL, 3M) was cooled to −10 ° C. and (S) -methyl 2- (7- (ethylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate in 1 mL of THF. A mixture of (Example 159, Step 1, 54 mg, 0.13 mmol) and NaBH ₄ (18 mg, 0.47 mmol) was added slowly. The mixture was stirred at −10 ° C. for 1 hour, slowly warmed to room temperature, concentrated and purified by silica gel column chromatography to give (S) -methyl 2- (7- (ethyl (methyl) amino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate was obtained as a white solid in 96% yield.

Step 2: Preparation of (S) -2- (7- (ethyl (methyl) amino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid (S) -methyl 2- (7- ( Ethyl (methyl) amino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoate (42 mg) was dissolved in 1 mL THF and LiOH solution (1 mL, 0.9 M, MeOH / H _2). O (in 1: 1)) was added. The resulting suspension was stirred at room temperature for 4 days and THF was removed under reduced pressure. The residual aqueous solution was acidified to pH ˜1 and filtered to give (S) -2- (7- (ethyl (methyl) amino) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid. Was obtained as a white solid in 95% yield. _{HRMS: [C 20 H 24 N} 2 O 5 S + H] + calcd 405.14787 for; found ^{(ESI-FTMS, [M +} H] 1+) 405.1465.

Example 162: Preparation of (S) -3-methyl-2- (8- (4-methylpiperazin-1-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid As described in Example 104. According to a procedure similar to that described above, using 1-methylpiperazine, (S) -3-methyl-2- (8- (4-methylpiperazin-1-yl) dibenzo [b, d] furan-3- Sulfonamido) butanoic acid was obtained as a white solid. _{HRMS: [C 22 H 27 N} 3 O 5 S + H] + calcd 446.17442 for; found ^{(ESI-FTMS, [M +} H] 1+) 446.17469.

Example 163: Preparation of (S) -2- (8- (1H-1,2,4-triazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid (S) -2- (8- (1H-1,2,4-triazol-1-yl) using 1H-1,2,4-triazole and following a procedure similar to that described in US Pat. Dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid was obtained as a white solid. _{HRMS: [C 19 H 18 N} 4 O 5 S + H] + calcd 415.10707 for; found ^{(ESI-FTMS, [M +} H] 1+) 415.10704.

Example 164: Preparation of (S) -2- (8- (4,4-difluoropiperidin-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid described in Example 104 (S) -2- (8- (4,4-Difluoropiperidin-1-yl) dibenzo [b, d] furan-3 using 4,4-difluoropiperidine according to a procedure similar to that described above. -Sulfonamido) -3-methylbutanoic acid was obtained as a white solid. _{HRMS: [C 22 H 24 F} 2 N 2 O 5 S + H] + calcd 467.14467 for; found ^{(ESI-FTMS, [M +} H] 1+) 467.14493.

Example 165: Preparation of (S) -3-Methyl-2- (8- (4-Methyl-1H-imidazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid (S) -3-methyl-2- (8- (4-methyl-1H-imidazol-1-yl) dibenzo was prepared using 4-methyl-1H-imidazole following a procedure similar to that described in [B, d] furan-3-sulfonamido) butanoic acid was obtained as a white solid. _{HRMS: [C 21 H 21 N} 3 O 5 S + H] + calcd 428.12747 for; found ^{(ESI-FTMS, [M +} H] 1+) 428.12781.

Example 166: Preparation of (S) -3-Methyl-2- (8- (2,2,2-trifluoroethylsulfonamido) dibenzo [b, d] furan-3-sulfonamido) butanoic acid (S) -3-methyl-2- (8- (2,2,2-trifluoroethyl) using 2,2,2-trifluoroethanesulfonyl chloride according to a procedure similar to that described in Sulfonamido) dibenzo [b, d] furan-3-sulfonamido) butanoic acid was obtained as a white solid. _HRMS: calcd 509.06585 for _{[C 19 H 19 F 3 N} 2 O 7 S 2 + H] +; Found ^{(ESI-FTMS, [M +} H] 1+) 509.06656.

Example 167: (S) -2- (8- (4-Fluoro-N- (4-fluorophenylsulfonyl) phenylsulfonamido) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Preparation Following a procedure analogous to that described in Example 18, using 4-fluorobenzene-1-sulfonyl chloride, (S) -2- (8- (4-fluoro-N- (4-fluorophenyl) Sulfonyl) phenylsulfonamido) dibenzo- [b, d] furan-3-sulfonamido) -3-methylbutanoic acid was obtained as a white solid. _{HRMS: [C 29 H 24 F} 2 N 2 O 9 S 3 + H] + calcd 679.06848 for; found ^{(ESI-FTMS, [M +} H] 1+) 679.06859.

Example 168: Preparation of (S) -2- (8- (4,5-dichlorothiophene-2-sulfonamido) dibenzo [b, d] furan-3-sulfonamido) -3-methylbutanoic acid Following procedures similar to those described, using 4,5-dichlorothiophene-2-sulfonyl chloride, (S) -2- (8- (4,5-dichlorothiophene-2-sulfonamido) dibenzo [ b, d] furan-3-sulfonamido) -3-methylbutanoic acid was obtained as a white solid. _{HRMS: [C 21 H 18 Cl} 2 N 2 O 7 S 3 + H] + calcd 576.97259 for; found ^{(ESI-FTMS, [M +} H] 1+) 576.97504.

Example 169: Preparation of (R) -2- (7- (5-methoxy-2H-tetrazol-2-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid Step 1: ( Preparation of R) -methyl 3-methyl-2- (7- (5-tosyl-2H-tetrazol-2-yl) dibenzo [b, d] furan-2-sulfonamido) butanoate (R) -2- (7 To a suspension of -azido-dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid methyl ester (Example 92, Step 1, 60 mg) was added 4-methylbenzenesulfonylcyanide (165 mg). The reaction mixture was stirred at 80 ° C. overnight, cooled to room temperature and water was added. The resulting mixture was acidified with 1N HCl to pH˜2 and filtered to give (R) -methyl 3-methyl-2- (7- (5-tosyl-2H-tetrazol-2-yl) dibenzo [ b, d] furan-2-sulfonamido) butanoate was obtained as a pale yellow compound.

Step 2: (R) -2- (7- (5-Methoxy-2H-tetrazol-2-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid and (R) -2- Preparation of (7- (5-hydroxy-2H-tetrazol-2-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid (R) -methyl 3-methyl obtained from step 1 2- (7- (5-tosyl-2H-tetrazol-2-yl) dibenzo [b, d] furan-2-sulfonamido) butanoate was dissolved in methanol / water (1: 1) and lithium hydroxide was dissolved. added. The reaction solution was stirred at room temperature for 16 hours, diluted with water, acidified with 1N HCl to pH˜2 and filtered. The crude product was purified by HPLC to give (R) -2- (7- (5-methoxy-2H-tetrazol-2-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutane. Acid (3 mg) as an off-white solid and (R) -2- (7- (5-hydroxy-2H-tetrazol-2-yl) dibenzo [b, d] furan-2-sulfonamido) -3- Methylbutanoic acid (1 mg) was obtained.

(R) -2- (7- (5-Methoxy-2H-tetrazol-2-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.71 (s, 1H), 8.58 (d, J = 8.34 Hz, 1H), 8.39 (d, J = 9.35 Hz, 1H) ), 8.21 (d, J = 1.77 Hz, 1H), 7.97-8.00 (m, 1H), 7.83 (dd, J = 8.34, 2.02 Hz, 1H), 4 .28 (s, 3H), 3.67 (dd, J = 9.47, 6.95 Hz, 1H), 1.86-1.96 (m, 1H) and 0.81 (dd, J = 1.11. 37, 6.82 Hz, 6H); MS (LCMS-ESI, M + H) 446.30.

Example 170: Preparation of (R) -2- (7- (5-hydroxy-2H-tetrazol-2-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid in Example 169 Isolating (R) -2- (7- (5-hydroxy-2H-tetrazol-2-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid as an off-white solid as a by-product did. ¹ H NMR (400 MHz, MeOD) δ ppm 8.82 (d, J = 1.26 Hz, 1H), 8.46-8.54 (m, 2H), 8.19-8.31 (m, 2H) , 7.9 (d, J = 8.84 Hz, 1H), 3.89 (d, 1H), 2.17-2.34 (m, 1H) and 1.16 (dd, 6H); MS (LCMS -ESI, M + H) 432.10.

Example 171: Preparation of (S) -3-methyl-2- (8- (2-oxo-1,3-oxazinan-3-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid Following a procedure similar to that described in Example 99 and using chloropropyl chloroformate, (S) -3-methyl-2- (8- (2-oxo-1,3-oxazinan-3-yl) Dibenzo [b, d] furan-3-sulfonamido) butanoic acid was obtained as a white solid. _{HRMS [C 21 H 22 N 3} O 2 S + H] + calcd 447.12205 for; found ^{(ESI-FTMS, [M +} H] 1+) 447.12419.

Example 172: Preparation of (S) -3-methyl-2- (7- (benzyl (methyl) amino) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid Step 1: (S) -tert- Preparation of butyl 2- (7- (benzylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate (S) -tert-butyl 2- (7-aminodibenzo [b, d ] Thiophene-3-sulfonamido) -3-methylbutanoate (Example 65, Step 4, 1.1 g, 2.5 mmol) and benzaldehyde (300 mg, 2.75 mmol) were dissolved in dry THF (20 mL), Heated to reflux for 4 hours and cooled. NaBH ₄ (1 g) and MeOH (2 mL) were added at 0 ° C. and the reaction mixture was stirred at room temperature for 2 h and partitioned between ethyl acetate (50 mL) and NaHCO ₃ (30 mL, 5%). The aqueous solution was extracted with ethyl acetate. The combined organic layers are washed with brine, dried over Na ₂ SO ₄ and concentrated to give (S) -tert-butyl 2- (7- (benzylamino) dibenzo [b, d] thiophene-3- Sulfonamido) -3-methylbutanoate was obtained (1.1 g). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.82 (d, J = 6.9 Hz, 3H), 0.85 (d, J = 6.9 Hz, 3H), 1.07 (s, 9H ), 1.92 (m, 1H), 3.5 (dd, J = 9.7 6.0 Hz, 1H), 4.39 (d, J = 5.8 Hz, 2H), 6.89 (m, 2H), 7.06 (d, J = 2.0 Hz, 1H), 7.39-7.21 (m, 4H), 7.42 (d, J = 7.5 Hz, 2H), 7.72 ( dd, J = 8.4 1.7 Hz, 1H), 8.03 (d, J = 9.6 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H) and 8.16 (d, J = 1.5 Hz, 1H).

Step 2: Preparation of (S) -tert-butyl 2- (7- (benzyl (methyl) amino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate obtained from step 1 (S) -tert-butyl 2- (7- (benzylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate (525 mg, 1 mmol) was added to formaldehyde (40% in water, 150 mg, 2 mmol) and THF (10 mL) and Na (CN) BH ₃ (1 g) and MeOH (2 mL) were added at 0 ° C. The reaction mixture was stirred at room temperature for 7 days. After performing a workup similar to that described in Step 1, (S) -tert-butyl 2- (7- (benzyl (methyl) amino) dibenzo [b, d] thiophene-3-sulfonamide) -3-Methylbutanoate was obtained as a white solid.

Step 3: Preparation of (S) -2- (7- (benzyl (methyl) amino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid (S) -tert-butyl 2- (7 -(Benzyl (methyl) amino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate was treated with 30% TFA in DCM at room temperature for 4 hours. After removal of solvent and excess TFA, (S) -2- (7- (benzyl (methyl) amino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was obtained as a TFA salt. . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.81 (d, J = 6.9 Hz, 3H), 0.83 (d, J = 6.9 Hz, 3H), 1.94 (m, 1H ), 3.15 (s, 3H), 3.57 (dd, J = 9.6 6.1 Hz, 1H), 4.74 (s, 2H), 7.02 (dd, J = 8.9 2) .3 Hz, 1 H), 7.36-7.20 (m, 6 H), 7.74 (dd, J = 8.5 1.7 Hz, 1 H), 7.95 (d, J = 9.3 Hz, 1 H) ), 8.14 (d, J = 8.9 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.25 (d, J = 1.7 Hz, 1H) and 12.43. (Br, 1H); MS (ES +) 483.1.

Example 173: Preparation of N-{[7- (1,1-dioxideisothiazolidin-2-yl) dibenzo [b, d] thien-3-yl] sulfonyl} -L-valine (S) -tert- Described in Example 99 using butyl 2- (7-aminodibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate (Example 65, Step 4) and 2-chloroethanesulfonyl chloride. N-{[7- (1,1-dioxideisothiazolidin-2-yl) dibenzo [b, d] thien-3-yl] sulfonyl} -L-valine was prepared according to a procedure similar to that described. . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.81 (d, J = 6.9 Hz; 3H), 0.84 (d, J = 6.9 Hz; 3H), 1.96 (d, J = 6.6 Hz; 1H), 2.48 (m, 2H), 3.60 (m, 1H), 3.60 (t, J = 7.4 Hz, 2H), 3.89 (t, J = 6) .3 Hz, 2H), 7.49 (dd, J = 8.3, 1.8 Hz, 1H), 7.88 (m, 2H), 8.07 (d, J = 9.4 Hz; 1H), 8 .44 (m, 3H), 12.53 (s br, 1H); MS (ES +) 482.92.

Example 174: Preparation of N-{[7- (1-oxideisothiazolidin-2-yl) dibenzo [b, d] thien-3-yl] sulfonyl} -L-valine The procedure described in Example 173 was followed. According to a similar procedure, N-{[7- (1-oxideisothiazolidine-2-yl) dibenzo [b, d] thien-3-yl] sulfonyl using 2-chloroethanesulfinic chloride. } -L-valine was prepared. MS (ES +) 467.18.

Example 175: Preparation of (S) -3-Methyl-2- (7- (2-oxooxazolidin-3-yl) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid As described in Example 99. (S) -tert-butyl 2- (7-aminodibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate (Example 65, Step 4) and Bromoethyl chloroformate was used to convert (S) -3-methyl-2- (7- (2-oxooxazolidin-3-yl) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid to white Prepared as a powder. MS (ES +) 449.05.

Example 176: Preparation of (S) -2- (7- (methoxycarbonyl (methyl) amino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid Step 1: (S) -tert- Preparation of butyl 2- (7-formamidodibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate Acetic anhydride (0 ° C. acetic anhydride (800 mg, 735 μl, 2.6 mmol) was prepared by adding 98% formic acid (450 mg, 370 μl, 3.2 mmol) dropwise followed by gentle heating at 50 ° C. for 2 hours) in THF (5 mL) ( S) -tert-Butyl 2- (7-aminodibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate (1.3 g, 3 mm l)) was added. After the reaction was found complete by TLC, it was concentrated to give 1.38 g of (S) -tert-butyl 2- (7-formamidodibenzo [b, d] thiophene-3-sulfonamide) -3 -Methylbutanoate was obtained.

Step 2: Preparation of (S) -tert-butyl 3-methyl-2- (7- (methylamino) dibenzo [b, d] thiophene-3-sulfonamido) butanoate (S) -tert obtained from step 1 -Butyl 2- (7-formamide dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate (1.38 g, 3 mmol) was dissolved in dry THF (10 mL). The solution was cooled at 0 ° C. and borane dimethyl sulfide complex (750 μl) was added dropwise. The reaction mixture was stirred at 0 ° C. for 1 hour and methanol was added. The resulting mixture was poured into water and extracted with DCM. The combined organic layers were dried over Na ₂ SO ₄ and concentrated to give (S) -tert-butyl 3-methyl-2- (7- (methylamino) dibenzo [b, d] thiophene-3-sulfonamide. ) Butanoate was obtained (1.3 g).

Steps 3 and 4: Preparation of (S) -2- (7- (methoxycarbonyl (methyl) amino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid (S) -tert-butyl 3 - suspended methyl 2- (7- (methylamino) dibenzo [b, d] thiophene-3-sulfonamido) butanoate (120 mg, 0.3 mmol) and _K 2 CO ₃ in dry THF (3 mL), chloroformate Methyl (0.6 mmol) was added. The reaction mixture is stirred at 65 ° C. for 2 hours, concentrated and purified by silica gel column chromatography to give (S) -tert-butyl 2- (7- (methoxycarbonyl (methyl) amino) dibenzo [b, d]. Thiophene-3-sulfonamido) -3-methylbutanoate was obtained, which was treated with LiOH and purified by preparative HPLC to give (S) -2- (7- (methoxycarbonyl (methyl) Amino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.80 (d, J = 7.0 Hz, 3H), 0.83 (d, J = 7.0 Hz, 3H), 1.87-2.03 (M, 1H), 3.33 (s, 3H), 3.55 to 3.64 (m, 1H), 3.65 (s, 3H), 7.54 (dd, J = 8.7, 1 .9 Hz, 1H), 7.87 (dd, J = 8.4, 1.6 Hz, 1H), 8.08 (d, J = 1.8 Hz, 1H), 8.09-8.13 (m, 1H), 8.44 (d, J = 8.8 Hz, 1H), 8.46 (d, J = 1.5 Hz, 1H), 8.50 (d, J = 8.5 Hz, 1H) and 12. 51 (br.s., 1H); MS (ES +) 451.0.

Example 177: Preparation of (S) -2- (7- (ethoxycarbonyl (methyl) amino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid The procedure described in Example 176 was followed. According to a similar procedure, ethyl (S) -2- (7- (ethoxycarbonyl (methyl) amino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was prepared using ethyl chloroformate. Obtained as a solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.80 (d, J = 6.9 Hz; 3H), 0.83 (d, J = 6.9 Hz; 3H), 1.19 (t, J = 7.1 Hz; 3H), 1.95 (m, 1H), 3.36 (s, 3H), 3.59 (m, 1H), 4.11 (q, J = 7.1 Hz; 2H), 7.54 (dd, J = 8.5, 2.1 Hz; 1H), 7.87 (dd, J = 8.2, 1.7 Hz; 1H), 8.07 (d, J = 1.9 Hz; 1H), 8.10 (s br, 1H), 8.43 (d, J = 8.7 Hz; 1H), 8.46 (d, J = 1.4 Hz; 1H) and 8.50 (d, J = 8.3 Hz; 1 H); MS (ES +) 465.1.

Example 178: Preparation of (S) -2- (7- (isopropoxycarbonyl (methyl) amino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid Procedure described in Example 176 (S) -2- (7- (Isopropoxycarbonyl (methyl) amino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid using isopropyl chloroformate according to a procedure similar to Was obtained as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ + TFA) δ ppm 0.80 (d, J = 6.7 Hz, 3H), 0.83 (d, J = 6.7 Hz, 3H), 1.20 (d, J = 6.2 Hz, 6H), 1.88-2.02 (m, 1H), 3.32 (s, 3H), 3.61 (dd, J = 9.5, 6.0 Hz, 1H), 4.87-4.89 (m, 1H), 7.53 (dd, J = 8.5, 2.1 Hz, 1H), 8.09-8.13 (m, 1H), 8.44 (d , J = 8.8 Hz, 1H), 8.46 (d, J = 1.5 Hz, 1H), 8.50 (d, J = 8.5 Hz, 1H) and 12.51 (br.s., 1H) ); MS (ES +) 479.0.

Example 179: Preparation of (S) -2- (7-(((4-fluorophenoxy) carbonyl) (methyl) amino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid Following a procedure similar to that described in 176, using 4-fluorophenyl chloroformate and using (S) -2- (7-(((4-fluorophenoxy) carbonyl) (methyl) amino) dibenzo [ b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was obtained as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.80 (d, J = 7.0 Hz, 3H), 0.83 (d, J = 6.7 Hz, 3H), 1.87-2.01 (M, 1H), 3.46 (s, 3H), 3.61 (dd, J = 9.4, 5.9 Hz, 1H), 7.21-7.26 (m, 4H), 7.71 (Dd, J = 8.5, 2.1 Hz, 1H), 7.88 (dd, J = 8.2, 1.8 Hz, 1H), 8.11 (d, J = 9.4 Hz, 1H), 8.26 (d, J = 2.1 Hz, 1H), 8.46-8.56 (m, 3H) and 12.52 (br.s., 1H); MS (ES +) 548.2.

Example 180: Preparation of (S) -3-methyl-2- (7- (methylamino) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid (S) -tert-butyl 3-methyl-2 -(7)-(Methylamino) dibenzo [b, d] thiophene-3-sulfonamido) butanoate (Example 176, step 2) was treated with TFA in dichloromethane to give (S) -3-methyl-2 -(7- (Methylamino) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid was prepared as the TFA salt. MS (ES +) 393.0.

Example 181 Preparation of N-{[7- (1,1-dioxidethiomorpholin-4-yl) dibenzo [b, d] thien-3-yl] sulfonyl} -L-valine Orthophosphoric acid (2.0 mL ) In (S) -methyl 2- (7-aminodibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoate (392 mg, 1 mmol) and divinyl sulfone (142 mg, 1.2 mmol) Was heated at 140 ° C. for 3 days. After workup and preparative HPLC purification, N-{[7- (1,1-dioxidethiomorpholin-4-yl) dibenzo [b, d] thien-3-yl] sulfonyl} -L-valine is white. Obtained as a solid (298 mg, 60% yield). MS (ES +) 497.14.

Example 182: Preparation of (S) -3-methyl-2- (7- (1,3,3-trimethylureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid As described in Example 176 According to a procedure similar to that described above, (S) -3-methyl-2- (7- (1,3,3-trimethylureido) dibenzo [b, d] thiophene-3- Sulfonamido) butanoic acid was obtained as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.76 (d, J = 6.9 Hz; 3H), 0.86 (d, J = 6.9 Hz; 3H), 2.3 (m, 1H ), 2.70 (s, 6H), 3.19 (s, 3H), 3.47 (m, 1H), 7.21 (dd, J = 8.9, 2.1 Hz; 1H), 7. 76 (d, J = 2.1 Hz; 1H), 7.82 (dd, J = 8.5, 1.7 Hz; 1H), 8.32 (s br, 1H), 8.36 (d, J = 8.7 Hz; 1H), 8.38 (d, J = 7.8 Hz; 1H) and 8.39 (d, J = 2.1 Hz; 1H); MS (ES +) 464.0.

Example 183: Preparation of (S) -2- (7- (3-Ethyl-1-methylureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid described in Example 176 Following a procedure similar to that using ethyl isocyanate, (S) -2- (7- (3-ethyl-1-methylureido) dibenzo [b, d] thiophene-3-sulfonamido) -3- Methylbutanoic acid was obtained as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ + TFA) δ ppm 0.80 (d, J = 6.9 Hz; 3H), 0.82 (d, J = 6.9 Hz; 3H), 1.01 (t, J = 7.4 Hz; 3H), 1.95 (m, 1H), 3.07 (m, 2H), 3.25 (s, 3H), 3.61 (dd, J = 9.4, 5. 9 Hz; 1 H), 6.26 (s br, 1 H), 7.45 (dd, J = 8.4, 1.9 Hz; 1 H), 7.86 (dd, J = 8.6, 1.7 Hz; 1H), 7.98 (d, J = 1.9 Hz; 1H), 8.08 (d, J = 9.6 Hz; 1H), 8.41 (d, J = 8.6 Hz; 1H), 8. 44 (d, J = 1.5 Hz; 1H), 8.46 (s br, 1H) and 8.48 (d, J = 8.4 Hz; 1H); MS (ES +) 464.1.

Example 184: Preparation of (S) -2- (7- (3-Benzyl-1-methylureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid described in Example 176 Following a procedure similar to that using benzyl isocyanate, (S) -2- (7- (3-benzyl-1-methylureido) dibenzo [b, d] thiophene-3-sulfonamido) -3- Methylbutanoic acid was obtained as a white solid. MS (ES +) 526.09.

Example 185: Preparation of (S) -2- (7- (3-Benzyl-1,3-dimethylureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid described in Example 176 (S) -2- (7- (3-Benzyl-1,3-dimethylureido) dibenzo [b, d] thiophene--, using benzyl (methyl) carbamic acid chloride, following a procedure similar to that described. 3-sulfonamido) -3-methylbutanoic acid was obtained as a white solid. MS (ES +) 540.10.

Example 186: Preparation of (S) -3-methyl-2- (7- (2-oxoimidazolidin-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid described in Example 99 (S) -3-Methyl-2- (7- (2-oxoimidazolidin-1-yl) dibenzo [b, d] thiophene-3 using chloropropyl isocyanate and following a procedure similar to that described -Sulfonamido) butanoic acid was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ + TFA) δ ppm 0.81 (d, J = 6.9 Hz; 3H), 0.84 (d, J = 6.9 Hz; 3H), 1.95 (m, 1H), 3.47 (m, 2H), 3.60 (dd, J = 9.5, 5.9 Hz, 1H), 3.99 (m, 2H), 7.83 (dd, J = 8. 5, 1.9 Hz; 1 H), 7.92 (dd, J = 8.8, 1.9 Hz, 1 H), 8.04 (d, J = 9.2 Hz; 1 H), 8.17 (d, J = 1.8 Hz; 1H), 8.35 (d, J = 9.0 Hz; 1H), 8.38 (d, J = 1.9 Hz; 1H) and 8.39 (d, J = 8.2 Hz, 1H); MS (ES +) 448.08.

Example 187: Preparation of (S) -3-Methyl-2- (7- (2-oxotetrahydropyrimidin-1 (2H) -yl) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid (S) -3-Methyl-2- (7- (2-oxotetrahydropyrimidin-1 (2H) -yl) dibenzo [b] using a procedure similar to that described in 99, using chloropropyl isocyanate. , D] thiophene-3-sulfonamido) butanoic acid was obtained as a white solid. MS (ES +) 462.0.

Example 188: Preparation of (R) -2- (7- (methoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid A procedure similar to that described in Example 65 According to, D-valine was used to give (R) -2- (7- (methoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.80 (d, J = 6.7 Hz, 3H), 0.84 (d, J = 6.7 Hz, 3H), 1.88-2.02 (M, 1H), 3.60 (dd, J = 8.9, 6.0 Hz, 1H), 3.73 (s, 3H), 7.58 (dd, J = 8.7, 1.9 Hz, 1H), 7.84 (dd, J = 8.5, 1.5 Hz, 1H), 8.05 (d, J = 9.4 Hz, 1H), 8.22 (d, J = 1.8 Hz, 1H) ), 8.35 (d, J = 8.5 Hz, 1H), 8.38 (d, J = 5.6 Hz, 1H), 8.40 (s, 1H), 10.04 (s, 1H) and 12.48 (br.s., 1H); MS (ES +) 437.0.

Example 189: Preparation of (R) -2- (7- (ethoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid A procedure similar to that described in Example 65 According to, ethyl chloroformate was used to give (R) -2- (7- (ethoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid as a white solid. MS (ES +) 451.01.

Example 190: Preparation of (R) -2- (7- (3-cyclopentylureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid Analogous to the procedure described in Example 65 According to the procedure, (R) -2- (7- (3-cyclopentylureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methylbutanoic acid was obtained as a white solid using cyclopentyl isocyanate. MS (ES +) 490.1.

Example 191: Preparation of (R) -3-methyl-2- (7- (3-phenylureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid Analogous to the procedure described in Example 65 The (R) -3-methyl-2- (7- (3-phenylureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid was obtained as a white solid using phenyl isocyanate according to the procedure described above. It was. MS (ES +) 498.1.

Example 192: Pharmacological Activity MMP-12 FRET Assay Compounds of the present teachings were tested in the following MMP-12 FRET assay. Each well of a black polystyrene 96 well plate contains assay buffer (50 mM HEPES (pH 7.4), 100 mM NaCl, 5 mM CaCl ₂ and 0.005% Brij-35), purified human MMP-12 enzyme and various concentrations of test. Compound (prepared by serial dilution of stock solution in 100% DMSO) was added. Plates were incubated for 30 minutes at room temperature. MCA-Pro-Leu-Gly-Leu-Dpa (DNP) -Ala-Arg, which is a substrate containing a fluorescent group (7-methoxycoumarin, MCA) and a 2,4-dinitrophenyl group (DNP), has a final concentration of 20 μM. The enzyme reaction was started by adding as follows. The final concentration of DMSO in this assay was 10%. The reaction was monitored at room temperature for 30 minutes, and the initial rate of the cleavage reaction was measured using a fluorescent plate reader (λ _ex : 325 nm, λ _em : 395 nm). A plot of inhibitor concentration against the initial rate of cleavage was fitted to the following equation: y = V _max ^* (1− (x ⁿ / (K ⁿ + x ⁿ ))), where x = inhibitor concentration, y = Initial velocity, V _max = initial velocity in the absence of inhibitor, n = slope factor and K = IC ₅₀ for inhibition curve.

  The results obtained are summarized in Table 2 below. The data presented represents the average value when one or more samples are tested.

Activity against other MMPs against various MMPs other than MMP-12 (including MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-13 and MMP-14) The compounds of the present teachings were tested. A wide variety of activities were observed, for example IC ₅₀ values from 0.3 to> 50000 were measured when compounds of the present teachings were tested against MMP-13.

  Those skilled in the art will envision changes, modifications and other implementations of what is described herein without departing from the spirit and essential characteristics of the present teachings. Accordingly, the scope of the present invention is defined by the following claims, rather than by the foregoing illustrative description, and all modifications encompassed within the meaning and scope equivalent to the claims are embraced herein. Is intended.

Claims (70)

Formula I:
(Where:
R ¹ is an N-linked, free carboxyl or carboxyl-protected, natural or non-natural amino acid, or N-linked amino acid derivative;
R ² and R ³ are independently a) H, b) oxo, c) —OR ⁸ , d) —S (O) _m R ⁸ , e) —S (O) _m OR ⁸ , f) — _{^{S (O) m NR 8 R}} 9, g) -C (O) R 8, h) -C (O) OR 8, i) -C (O) NR 8 R 9, j) -C (S) OR ⁸ , k) -C (S) R ⁸ , 1) -C (S) NR ⁸ R ⁹ , m) -C (NR ⁸ ) NR ⁸ R ⁹ , n) C _1-10 alkyl group, o) C _{2 -10} alkenyl group, p) C _2-10 alkynyl group, q) C _1-10 haloalkyl group, r) C _3-10 cycloalkyl group, s) C _6-14 aryl group, t) 3-14 membered cyclo a heteroalkyl group, or u) 5 to 13 membered heteroaryl group, wherein, n) each ~u) is substituted with 1-4 ^{-Z-R 10} group optionally; or ^{R 2} and ^{R 3,} together with their common nitrogen ^{atom, a) -N = CR 7 R} 7, b) -N = N-R 8, c) -N = O, d) 3 Forming a -14 membered cycloheteroalkyl group or e) a 5-13 membered heteroaryl group, wherein each of d) and e) is optionally 1-4 -ZR ¹⁰ groups Is replaced by;
R ⁴ and R ⁵ are independently a) H, b) —CN, c) —NO ₂ , d) halogen, e) —OR ⁸ , f) —NR ⁸ R ⁹ , g) —S (O _{^{) m R 8, h) -S}} (O) m OR 8, i) -C (O) R 8, j) -C (O) OR 8, k) -C (O) NR 8 R 9, l) ^{-C (S) R 8, m} ) -C (S) OR 8, n) -C (S) NR 8 R 9, o) C 1-10 alkyl _{group, p) C 2-10} alkenyl group, q) C _2-10 alkynyl group, r) C _1-10 haloalkyl group, s) C _3-10 cycloalkyl group, t) C _6-14 aryl group, u) 3-14 membered cycloheteroalkyl group or v) 5 A 13-membered heteroaryl group, wherein each of o) to v) is optionally substituted with 1 to 4 -ZR ¹⁰ groups;
R ⁶ is a) H, b) -S (O) _m R ⁸ , c) -S (O) _m OR ⁸ , d) -C (O) R ⁸ , e) -C (O) OR ⁸ , ^{f) -C (O) NR 8} R 9, g) -C (S) R 8, h) -C (S) OR 8, i) -C (S) NR 8 R 9, j) C 1-10 An alkyl group, k) a C _2-10 alkenyl group, 1) a C _2-10 alkynyl group or m) a C _1-10 haloalkyl group, wherein each of j) -m) is optionally C ₆ Substituted with a _-14 aryl group or a 5-13 membered heteroaryl group, wherein each of the C _6-14 aryl group and the 5-13 membered heteroaryl group is optionally substituted with 1-4 -Z Substituted with -R ¹⁰ groups;
R ⁷ is in each occurrence a) H, b) —CN, c) —NO ₂ , d) halogen, e) oxo, f) —OR ⁸ , g) —NR ⁸ R ⁹ , h) —N. _{^{(O) R 8 R 9,}} i) -S (O) m R 8, j) -S (O) m O-R 8, k) -S (O) m NR 8 R 9, l) -C ( ^{O) R 8, m) -C} (O) OR 8, n) -C (O) NR 8 R 9, o) -C (S) R 8, p) -C (S) OR 8, q) - C (S) NR ⁸ R ⁹ , r) -Si (C _1-10 alkyl) ₃ , s) C _1-10 alkyl group, t) C _2-10 alkenyl group, u) C _2-10 alkynyl group, v ) C _1-10 haloalkyl group, w) C _3-10 cycloalkyl group, x) C _6-14 aryl group, y) 3-14 membered cycloheteroalkyl group or z) 5-13 membered heteroary. Wherein each of r) to z) is optionally substituted with 1 to 4 -ZR ¹⁰ groups;
R ⁸ and R ⁹ are independently in each occurrence a) H, b) —OR ¹¹ , c) —SR ¹¹ , d) —S (O) _m R ¹¹ , e) —S (O) _{^{m -OR 11, f) -S (}} O) m -NR 11 R 12, g) -C (O) R 11, h) -C (O) OR 11, i) -C (O) NR 11 R 12 J) —C (S) NR ¹¹ R ¹² , k) C _1-10 alkyl group, 1) C _2-10 alkenyl group, m) C _2-10 alkynyl group, n) C _1-10 alkoxy group, o A) a C _1-10 haloalkyl group, p) a C _3-10 cycloalkyl group, q) a C _6-14 aryl group, r) a 3-14 membered cycloheteroalkyl group or s) a 5-13 membered heteroaryl group. Wherein each of k) to s) is optionally substituted with 1 to 4 —ZR ¹⁰ groups;
R ¹⁰ is, in each occurrence, a) halogen, b) —CN, c) —NO ₂ , d) oxo, e) —O—Z—R ¹¹ , f) —NR ¹¹ —ZR ¹² , g _{^{) -N (O) R 11 -Z}} -R 12, h) -S (O) m R 11, i) -S (O) m O-Z-R 11, j) -S (O) m NR 11 ^{-Z-R 12, k) -C} (O) R 11, l) -C (O) O-Z-R 11, m) -C (O) NR 11 -Z-R 12, n) -C ( S) NR < ¹¹ > -ZR < ¹² >, o) -Si ( _C1-10 alkyl) ₃ , p) _C1-10 alkyl group, q) _C2-10 alkenyl group, r) _C2-10 alkynyl group, _{s) C 1-10} haloalkyl _{group, t) C 3-10} cycloalkyl _{group, u) C 6-14} aryl group, v) 3 to 14 membered cycloheteroalkyl group, or ) A 5 to 13 membered heteroaryl group, wherein each of o) to w) is replaced with 1-4 ^{R 13} groups optionally;
R ¹¹ and R ¹² are independently in each occurrence a) H, b) —OH, c) —SH, d) —S (O) ₂ OH, e) —C (O) OH, f _{) -C (O) NH 2,} g) -C (S) NH 2, h) -OC 1-10 _{alkyl, i) -S (O) m} -C 1-10 alkyl, j) -S (O) _m- OC _1-10 alkyl, k) -C (O) -C _1-10 alkyl, l) -C (O) -OC _1-10 alkyl, m) -C (S) N (C _1-10 alkyl) ) ₂ , n) -C (S) NH-C _1-10 alkyl, o) -C (O) NH-C _1-10 alkyl, p) -C (O) N (C _1-10 alkyl) ₂ , _{q) C 1-10} alkyl _{group, r) C 2-10} alkenyl _{group, s) C 2-10} alkynyl _{group, t) C 1-10} alkoxy _{group, u) C 1-10} Haroaru Le _{group, v) C 3-10} cycloalkyl _{group, w) C 6-14} aryl group, x) 3 to 14 membered cycloheteroalkyl group, or y) 5 to 13 membered heteroaryl group, wherein, each of h) -y) is optionally substituted with 1-4 -R ¹³ groups;
R ¹³ is in each occurrence a) halogen, b) —CN, c) —NO ₂ , d) oxo, e) —OH, f) —NH ₂ , g) —NH (C _1-10 alkyl) , h) _{-N (C 1-10 alkyl) 2, i) -S (O} ) m H, j) -S (O) m -C 1-10 _{alkyl, k) -S (O) 2} OH, l ) -S (O) _m -OC _1-10 alkyl, m) -S (O) _m NH ₂ , n) -S (O) _m NH (C _1-10 alkyl), o) -S (O) _m N (C _1-10 alkyl) ₂ , p) —CHO, q) —C (O) —C _1-10 alkyl, r) —C (O) OH, s) —C (O) —OC _{1-10 alkyl, t) -C (O) NH} 2, u) -C (O) NH-C 1-10 _{alkyl, v) -C (O) N} (C 1-10 _alkyl) 2, _w) -C (S ) NH _{2 , X) -C (S) NH} -C 1-10 _{alkyl, y) -C (S) N} (C 1-10 _{alkyl) 2, z) -Si (C} 1-10 _alkyl) 3, _{aa) C 1 -10} alkyl group, ab) C _2-10 alkenyl group, ac) C _2-10 alkynyl group, ad) C _1-10 alkoxy group, ae) C _1-10 haloalkyl group, af) C _3-10 cycloalkyl group Ag) a C _6-14 aryl group, ah) a 3-14 membered cycloheteroalkyl group or ai) a 5-13 membered heteroaryl group;
X is O, S, S (O), S (O) ₂ or NR ⁶ ;
Y is S (O), S (O) ₂ or C (O);
Z is in each _occurrence a) a divalent C _1-10 alkyl group, b) a divalent C _2-10 alkenyl group, c) a divalent C _2-10 alkynyl group, d) a divalent C _{A 1-10} haloalkyl group or e) a covalent bond; and m is 0, 1 or 2 in each occurrence)
Or a pharmaceutically acceptable salt, hydrate or ester thereof. Formula I:
(Where:
R ¹ is an N-linked, free carboxyl or carboxyl-protected, natural or non-natural amino acid, or N-linked amino acid derivative;
R ² and R ³ are independently a) H, b) oxo, c) —S (O) _m OR ⁸ , d) —S (O) _m NR ⁸ R ⁹ , e) —C (O) ^{R 8, f) -C (S} ) OR 8, g) -C (S) R 8, h) -C (S) NR 8 R 9, i) -C (NR 8) NR 8 R 9, j) C _1-10 alkyl group, k) C _2-10 alkenyl group, 1) C _2-10 alkynyl group, m) C _1-10 haloalkyl group, n) C _3-10 cycloalkyl group, o) C _6-14 An aryl group, p) a 3-14 membered cycloheteroalkyl group or q) a 5-13 membered heteroaryl group, wherein each of j) -q) is optionally 1-4- substituted with ^{Z-R 10} group; or ^{R 2} and ^{R 3} together with their common nitrogen ^{atom, a) -N = CR 7 R} 7, b) - = ^{N-R 8} or c) to form a -N = O;
R ⁴ and R ⁵ are independently a) H, b) —CN, c) —NO ₂ , d) halogen, e) —OR ⁸ , f) —NR ⁸ R ⁹ , g) —S (O _{^{) m R 8, h) -S}} (O) m OR 8, i) -C (O) R 8, j) -C (O) OR 8, k) -C (O) NR 8 R 9, l) ^{-C (S) R 8, m} ) -C (S) OR 8, n) -C (S) NR 8 R 9, o) C 1-10 alkyl _{group, p) C 2-10} alkenyl group, q) C _2-10 alkynyl group, r) C _1-10 haloalkyl group, s) C _3-10 cycloalkyl group, t) C _6-14 aryl group, u) 3-14 membered cycloheteroalkyl group or v) 5 A 13 membered heteroaryl group, wherein each of o) to v) is optionally substituted with 1 to 4 optionally -ZR ¹⁰ groups;
R ⁶ is a) H, b) -S (O) _m R ⁸ , c) -S (O) _m OR ⁸ , d) -C (O) R ⁸ , e) -C (O) OR ⁸ , ^{f) -C (O) NR 8} R 9, g) -C (S) R 8, h) -C (S) OR 8, i) -C (S) NR 8 R 9, j) C 1-10 An alkyl group, k) a C _2-10 alkenyl group, 1) a C _2-10 alkynyl group or m) a C _1-10 haloalkyl group, wherein each of j) -m) is optionally C ₆ Substituted with a _-14 aryl group or a 5-13 membered heteroaryl group, wherein each of the C _6-14 aryl group and the 5-13 membered heteroaryl group is optionally substituted with 1-4 -Z Substituted with -R ¹⁰ groups;
R ⁷ is in each occurrence a) H, b) —CN, c) —NO ₂ , d) halogen, e) oxo, f) —OR ⁸ , g) —NR ⁸ R ⁹ , h) —N. _{^{(O) R 8 R 9,}} i) -S (O) m R 8, j) -S (O) m O-R 8, k) -S (O) m NR 8 R 9, l) -C ( ^{O) R 8, m) -C} (O) OR 8, n) -C (O) NR 8 R 9, o) -C (S) R 8, p) -C (S) OR 8, q) - C (S) NR ⁸ R ⁹ , r) -Si (C _1-10 alkyl) ₃ , s) C _1-10 alkyl group, t) C _2-10 alkenyl group, u) C _2-10 alkynyl group, v ) C _1-10 haloalkyl group, w) C _3-10 cycloalkyl group, x) C _6-14 aryl group, y) 3-14 membered cycloheteroalkyl group or z) 5-13 membered heteroary. Wherein each of r) to z) is optionally substituted with 1 to 4 -ZR ¹⁰ groups;
R ⁸ and R ⁹ are independently in each occurrence a) H, b) —OR ¹¹ , c) —SR ¹¹ , d) —S (O) _m R ¹¹ , e) —S (O) _{^{m -OR 11, f) -S (}} O) m -NR 11 R 12, g) -C (O) R 11, h) -C (O) OR 11, i) -C (O) NR 11 R 12 J) —C (S) NR ¹¹ R ¹² , k) C _1-10 alkyl group, 1) C _2-10 alkenyl group, m) C _2-10 alkynyl group, n) C _1-10 alkoxy group, o A) a C _1-10 haloalkyl group, p) a C _3-10 cycloalkyl group, q) a C _6-14 aryl group, r) a 3-14 membered cycloheteroalkyl group or s) a 5-13 membered heteroaryl group. Wherein each of k) to s) is optionally substituted with 1 to 4 —ZR ¹⁰ groups;
R ¹⁰ is, in each occurrence, a) halogen, b) —CN, c) —NO ₂ , d) oxo, e) —O—Z—R ¹¹ , f) —NR ¹¹ —ZR ¹² , g _{^{) -N (O) R 11 -Z}} -R 12, h) -S (O) m R 11, i) -S (O) m O-Z-R 11, j) -S (O) m NR 11 ^{-Z-R 12, k) -C} (O) R 11, l) -C (O) O-Z-R 11, m) -C (O) NR 11 -Z-R 12, n) -C ( S) NR < ¹¹ > -ZR < ¹² >, o) -Si ( _C1-10 alkyl) ₃ , p) _C1-10 alkyl group, q) _C2-10 alkenyl group, r) _C2-10 alkynyl group, _{s) C 1-10} haloalkyl _{group, t) C 3-10} cycloalkyl _{group, u) C 6-14} aryl group, v) 3 to 14 membered cycloheteroalkyl group, or ) A 5 to 13 membered heteroaryl group, wherein each of o) to w) is replaced with 1-4 ^{R 13} groups optionally;
R ¹¹ and R ¹² are independently in each occurrence a) H, b) —OH, c) —SH, d) —S (O) ₂ OH, e) —C (O) OH, f _{) -C (O) NH 2,} g) -C (S) NH 2, h) -S (O) m -C 1-10 _{alkyl, i) -S (O) m} -OC 1-10 alkyl, j ) -OC _1-10 alkyl, k) -C (O) -C _1-10 alkyl, l) -C (O) -OC _1-10 alkyl, m) -C (S) N (C _1-10 alkyl) ) ₂ , n) -C (S) NH-C _1-10 alkyl, o) -C (O) NH-C _1-10 alkyl, p) -C (O) N (C _1-10 alkyl) ₂ , _{q) C 1-10} alkyl _{group, r) C 2-10} alkenyl _{group, s) C 2-10} alkynyl _{group, t) C 1-10} alkoxy _{group, u) C 1-10} Haroaru Le _{group, v) C 3-10} cycloalkyl _{group, w) C 6-14} aryl group, x) 3 to 14 membered cycloheteroalkyl group, or y) 5 to 13 membered heteroaryl group, wherein, each of h) -y) is optionally substituted with 1-4 -R ¹³ groups;
R ¹³ is in each occurrence a) halogen, b) —CN, c) —NO ₂ , d) oxo, e) —OH, f) —NH ₂ , g) —NH (C _1-10 alkyl) , h) _{-N (C 1-10 alkyl) 2, i) -S (O} ) m H, j) -S (O) m -C 1-10 _{alkyl, k) -S (O) 2} OH, l ) -S (O) _m -OC _1-10 alkyl, m) -S (O) _m NH ₂ , n) -S (O) _m NH (C _1-10 alkyl), o) -S (O) _m N (C _1-10 alkyl) ₂ , p) —CHO, q) —C (O) —C _1-10 alkyl, r) —C (O) OH, s) —C (O) —OC _{1-10 alkyl, t) -C (O) NH} 2, u) -C (O) NH-C 1-10 _{alkyl, v) -C (O) N} (C 1-10 _alkyl) 2, _w) -C (S ) NH _{2 , X) -C (S) NH} -C 1-10 _{alkyl, y) -C (S) N} (C 1-10 _{alkyl) 2, z) -Si (C} 1-10 _alkyl) 3, _{aa) C 1 -10} alkyl group, ab) C _2-10 alkenyl group, ac) C _2-10 alkynyl group, ad) C _1-10 alkoxy group, ae) C _1-10 haloalkyl group, af) C _3-10 cycloalkyl group Ag) a C _6-14 aryl group, ah) a 3-14 membered cycloheteroalkyl group or ai) a 5-13 membered heteroaryl group;
X is O, S, S (O), S (O) ₂ or NR ⁶ ;
Y is S (O), S (O) ₂ or C (O);
Z is in each _occurrence a) a divalent C _1-10 alkyl group, b) a divalent C _2-10 alkenyl group, c) a divalent C _2-10 alkynyl group, d) a divalent C _{A 1-10} haloalkyl group or e) a covalent bond; and m is 0, 1 or 2 in each occurrence)
Or a pharmaceutically acceptable salt, hydrate or ester thereof. R ² and R ³ are independently H, oxo, —C (O) R ⁸ , C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group and C _3-10 cycloalkyl. Wherein each of the C _1-10 alkyl group, the C _2-10 alkenyl group, the C _2-10 alkynyl group and the C _3-10 cycloalkyl group is optionally substituted with 1-4- It is substituted with Z-R ¹⁰ group, the compound or a pharmaceutically acceptable salt, hydrate or ester according to claim 2. R ² and R ³ are independently H, oxo, —C (O) CH ₃ , —C (O) CH ₂ CH ₃ , —C (O) CH (CH ₃ ) ₂ , methyl group and ethyl group 3. A compound according to claim 2 or a pharmaceutically acceptable salt, hydrate or ester thereof selected from R ² and R ³ together with their common nitrogen atom form —N═CR ⁷ R ⁷ , where R ⁷ is, in each occurrence, H, halogen, —OR ⁸ , —NR ⁸ R ⁹ , C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group, C _1-10 haloalkyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, 3 A 14 to 14-membered cycloheteroalkyl group or a 5 to 13-membered heteroaryl group, and a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C _1-10 haloalkyl group, C Each of the _3-10 cycloalkyl group, the C _6-14 aryl group, the 3-14 membered cycloheteroalkyl group and the 5-13 membered heteroaryl group is optionally substituted with 1 to 4 —Z—R ^10. Replace with group Or a pharmaceutically acceptable salt, hydrate or ester thereof. R ² and R ³ together with the nitrogen atom common to them form —N═CHR ⁷ , where R ⁷ is —NH ₂ , —NH (C _1-10 alkyl) or — 3. A compound according to claim 2, or a pharmaceutically acceptable salt, hydrate or ester thereof, which is N ( _C1-10 alkyl) ₂ . —NR ² R ³ is —NH ₂ , —NO ₂ , —NHC (O) CH ₃ , —N (CH ₂ CH ₂ OH) C (O) CH ₃ , —NHCH ₃ , —NHCH ₂ CH ₃ , — _{N (CH 3) CH 2 CH} 3, -N (CH 2 CH 3) 2, -NHCH 2 CH 2 OH, -NHCH 2 CH 2 Cl or -N = CHN _{(CH 3)} is _2, in claim 2 Or a pharmaceutically acceptable salt, hydrate or ester thereof. (R) -2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7-aminodibenzo [b, d] furan-2-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8-aminodibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8- (diethylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8- (ethylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S, E) -2- (8-((dimethylamino) methyleneamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(R) -3-methyl-2- (7- (4- (trifluoromethyl) thiazol-2-ylamino) dibenzo [b, d] furan-2-sulfonamido) butanoic acid,
(S) -2- (7-aminodibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7- (2-chloroethylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7- (N- (2-hydroxyethyl) acetamido) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8-bromo-7-nitrodibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-Methyl-2- (7-nitrodibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(S) -2- (7-amino-8-bromodibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(R) -3-methyl-2- (7-nitrodibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(S) -2- (7- (ethylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7- (ethyl (methyl) amino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-methyl-2- (7- (benzyl (methyl) amino) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid, or (S) -3-methyl-2- (7- (Methylamino) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid or a pharmaceutically acceptable salt, hydrate or ester thereof. Formula I:
(Where:
R ¹ is an N-linked, free carboxyl or carboxyl-protected, natural or non-natural amino acid, or N-linked amino acid derivative;
R ² is a) —C (O) OR ⁸ or b) —C (O) NR ⁸ R ⁹ ;
R ³ is a) H, b) -S (O) _m R ⁸ , c) -S (O) _m OR ⁸ , d) -S (O) _m NR ⁸ R ⁹ , e) -C (O) ^{R 8, f) -C (S} ) OR 8, g) -C (S) R 8, h) -C (S) NR 8 R 9, i) -C (NR 8) NR 8 R 9, j) C _1-10 alkyl group, k) C _2-10 alkenyl group, 1) C _2-10 alkynyl group, m) C _1-10 haloalkyl group, n) C _3-10 cycloalkyl group, o) C _6-14 An aryl group, p) a 3-14 membered cycloheteroalkyl group or q) a 5-13 membered heteroaryl group, wherein each of j) -q) is optionally 1-4- Substituted with a Z—R ¹⁰ group; or R ³ and the R ⁸ portion of R ² are attached to them
Together to form a 3-14 membered cyclic urea group or a 3-14 membered cyclic carbamate group, each of which is optionally substituted with 1 to 4 —Z—R ¹⁰ groups. ;
R ⁴ and R ⁵ are independently a) H, b) —CN, c) —NO ₂ , d) halogen, e) —OR ⁸ , f) —NR ⁸ R ⁹ , g) —S (O _{^{) m R 8, h) -S}} (O) m OR 8, i) -C (O) R 8, j) -C (O) OR 8, k) -C (O) NR 8 R 9, l) ^{-C (S) R 8, m} ) -C (S) OR 8, n) -C (S) NR 8 R 9, o) C 1-10 alkyl _{group, p) C 2-10} alkenyl group, q) C _2-10 alkynyl group, r) C _1-10 haloalkyl group, s) C _3-14 cycloalkyl group, t) C _6-14 aryl group, u) 3-14 membered cycloheteroalkyl group or v) 5 A 13-membered heteroaryl group, wherein each of o) to v) is optionally substituted with 1 to 4 -ZR ¹⁰ groups;
R ⁶ is a) H, b) -S (O) _m R ⁸ , c) -S (O) _m OR ⁸ , d) -C (O) R ⁸ , e) -C (O) OR ⁸ , ^{f) -C (O) NR 8} R 9, g) -C (S) R 8, h) -C (S) OR 8, i) -C (S) NR 8 R 9, j) C 1-10 An alkyl group, k) a C _2-10 alkenyl group, 1) a C _2-10 alkynyl group or m) a C _1-10 haloalkyl group, wherein each of j) -m) is optionally C ₆ Substituted with a _-14 aryl group or a 5-13 membered heteroaryl group, wherein each of the C _6-14 aryl group and the 5-13 membered heteroaryl group is optionally substituted with 1-4 -Z Substituted with -R ¹⁰ groups;
R ⁸ and R ⁹ are independently in each occurrence a) H, b) —OR ¹¹ , c) —SR ¹¹ , d) —S (O) _m R ¹¹ , e) —S (O) _{^{m -OR 11, f) -S (}} O) m -NR 11 R 12, g) -C (O) R 11, h) -C (O) OR 11, i) -C (O) NR 11 R 12 J) —C (S) NR ¹¹ R ¹² , k) C _1-10 alkyl group, 1) C _2-10 alkenyl group, m) C _2-10 alkynyl group, n) C _1-10 alkoxy group, o A) a C _1-10 haloalkyl group, p) a C _3-10 cycloalkyl group, q) a C _6-14 aryl group, r) a 3-14 membered cycloheteroalkyl group or s) a 5-13 membered heteroaryl group. Wherein each of k) to s) is optionally substituted with 1 to 4 —ZR ¹⁰ groups;
R ¹⁰ is, in each occurrence, a) halogen, b) —CN, c) —NO ₂ , d) oxo, e) —O—Z—R ¹¹ , f) —NR ¹¹ —ZR ¹² , g _{^{) -N (O) R 11 -Z}} -R 12, h) -S (O) m R 11, i) -S (O) m O-Z-R 11, j) -S (O) m NR 11 ^{-Z-R 12, k) -C} (O) R 11, l) -C (O) O-Z-R 11, m) -C (O) NR 11 -Z-R 12, n) -C ( S) NR < ¹¹ > -ZR < ¹² >, o) -Si ( _C1-10 alkyl) ₃ , p) _C1-10 alkyl group, q) _C2-10 alkenyl group, r) _C2-10 alkynyl group, _{s) C 1-10} haloalkyl _{group, t) C 3-10} cycloalkyl _{group, u) C 6-14} aryl group, v) 3 to 14 membered cycloheteroalkyl group, or ) A 5 to 13 membered heteroaryl group, wherein each of o) to w) is replaced with 1-4 ^{R 13} groups optionally;
R ¹¹ and R ¹² are independently in each occurrence a) H, b) —OH, c) —SH, d) —S (O) ₂ OH, e) —C (O) OH, f _{) -C (O) NH 2,} g) -C (S) NH 2, h) -S (O) m -C 1-10 _{alkyl, i) -S (O) m} -OC 1-10 alkyl, j ) -OC _1-10 alkyl, k) -C (O) -C _1-10 alkyl, l) -C (O) -OC _1-10 alkyl, m) -C (S) N (C _1-10 alkyl) ) ₂ , n) -C (S) NH-C _1-10 alkyl, o) -C (O) NH-C _1-10 alkyl, p) -C (O) N (C _1-10 alkyl) ₂ , _{q) C 1-10} alkyl _{group, r) C 2-10} alkenyl _{group, s) C 2-10} alkynyl _{group, t) C 1-10} alkoxy _{group, u) C 1-10} Haroaru Le _{group, v) C 3-10} cycloalkyl _{group, w) C 6-14} aryl group, x) 3 to 14 membered cycloheteroalkyl group, or y) 5 to 13 membered heteroaryl group, wherein, each of h) -y) is optionally substituted with 1-4 -R ¹³ groups;
R ¹³ is in each occurrence a) halogen, b) —CN, c) —NO ₂ , d) oxo, e) —OH, f) —NH ₂ , g) —NH (C _1-10 alkyl) , h) _{-N (C 1-10 alkyl) 2, i) -S (O} ) m H, j) -S (O) m -C 1-10 _{alkyl, k) -S (O) 2} OH, l ) -S (O) _m -OC _1-10 alkyl, m) -S (O) _m NH ₂ , n) -S (O) _m NH (C _1-10 alkyl), o) -S (O) _m N (C _1-10 alkyl) ₂ , p) —CHO, q) —C (O) —C _1-10 alkyl, r) —C (O) OH, s) —C (O) —OC _{1-10 alkyl, t) -C (O) NH} 2, u) -C (O) NH-C 1-10 _{alkyl, v) -C (O) N} (C 1-10 _alkyl) 2, _w) -C (S ) NH _{2 , X) -C (S) NH} -C 1-10 _{alkyl, y) -C (S) N} (C 1-10 _{alkyl) 2, z) -Si (C} 1-10 _alkyl) 3, _{aa) C 1 -10} alkyl group, ab) C _2-10 alkenyl group, ac) C _2-10 alkynyl group, ad) C _1-10 alkoxy group, ae) C _1-10 haloalkyl group, af) C _3-10 cycloalkyl group Ag) a C _6-14 aryl group, ah) a 3-14 membered cycloheteroalkyl group or ai) a 5-13 membered heteroaryl group;
X is O, S, S (O), S (O) ₂ or NR ⁶ ;
Y is S (O), S (O) ₂ or C (O);
Z is in each _occurrence a) a divalent C _1-10 alkyl group, b) a divalent C _2-10 alkenyl group, c) a divalent C _2-10 alkynyl group, d) a divalent C _{A 1-10} haloalkyl group or e) a covalent bond; and m is 0, 1 or 2 in each occurrence)
Or a pharmaceutically acceptable salt, hydrate or ester thereof. R ³ is H or C _1-10 alkyl group, a compound or a pharmaceutically acceptable salt, hydrate or ester of claim 9. R ³ is, H, is selected from methyl and ethyl, the compound or a pharmaceutically acceptable salt, hydrate or ester of claim 9. R ² is -C (O) OR ^8, compound, or a pharmaceutically acceptable salt, hydrate or ester as claimed in any one of claims 9-11. R ⁸ is H, —C (O) R ¹¹ , —C (O) OR ¹¹ , —C (O) NR ¹¹ R ¹² , C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 Selected from an alkynyl group, a C _1-10 haloalkyl group, a C _3-10 cycloalkyl group, a C _6-14 aryl group, a 3-14 membered cycloheteroalkyl group and a 5-13 membered heteroaryl group, C _1-10 alkyl _{radical, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10} haloalkyl _{group, C 3-10 cycloalkyl, C 6-14} aryl group, 3-14 membered Shikurohetero 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein each of the alkyl group and the 5- to 13-membered heteroaryl group is optionally substituted with 1 to 4 -ZR ¹⁰ groups. Salt, hydrate Or ester. R ⁸ _{is, H, C 1-10 alkyl, C 2-10} alkenyl groups _are selected from _{C 2-10} alkynyl and _{C 6-14} aryl groups, _{wherein, C 1-10} alkyl _{group, C 2- 10} alkenyl _group, each _{C 2-10} alkynyl and _{C 6-14} aryl group is substituted with 1-4 ^{-Z-R 10} group optionally compound according to claim 12 or a Pharmaceutically acceptable salt, hydrate or ester. R ⁸ is selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a butyl group, a hexyl group, and a butynyl group, each of which is halogen, —S (O) _m R ¹¹ , —S ( O) _m OZR ¹¹ , -S (O) _m NR ¹¹ -ZR ¹² , -C (O) R ¹¹ , -C (O) OZR ¹¹ , -C (O) NR ^{11 -Z-R} _{12, C 6-14} optionally substituted with 1-4 groups independently selected from heteroaryl groups of aryl and 5-13 membered, according to claim 12 A compound or a pharmaceutically acceptable salt, hydrate or ester thereof. R ⁸ is methyl group, ethyl group, propyl group, isopropyl group, isobutyl group, butyl group, hexyl group, 3-butynyl group, 4-butynyl group, 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group The compound according to claim 12, or a pharmaceutically acceptable salt, hydrate or ester thereof, selected from: 2-methanesulfonylethyl group, 3-chloropropyl group and benzyl group. 13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is a phenyl group optionally substituted with 1 to 4 groups independently selected from halogen and C _1-10 alkyl group. Acceptable salt, hydrate or ester. R ⁸ is a phenyl group, a tolyl group, selected from a fluorophenyl group and a chlorophenyl group, a compound or a pharmaceutically acceptable salt, hydrate or ester as claimed in claim 12. The compound according to any one of claims 9 to 11, or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein R ² is -C (O) NR ⁸ R ⁹ . R ⁸ and R ⁹ are H, C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, 3-14 membered Independently selected from a cycloheteroalkyl group and a 5-13 membered heteroaryl group, a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C _3-10 cycloalkyl group, a C _6-14 aryl group, each of cycloheteroalkyl groups and 5-13 membered heteroaryl group 3-14 membered, substituted with 1-4 ^{-Z-R 10} group optionally claims 19. The compound according to 19, or a pharmaceutically acceptable salt, hydrate or ester thereof. R ⁹ is H or methyl group, the compound or a pharmaceutically acceptable salt, hydrate or ester as claimed in claim 19 or 20. R ⁸ is selected from H, a C _1-10 alkyl group, a C _3-10 cycloalkyl group, a C _6-14 aryl group, and a 5-13 membered heteroaryl group, and a C _1-10 alkyl group, C _{3- 10} cycloalkyl _group, each heteroaryl groups _{C 6-14} aryl and 5-13 membered are substituted with 1-4 ^{-Z-R 10} group optionally of claim 19 to 21 A compound according to any one or a pharmaceutically acceptable salt, hydrate or ester thereof. R ⁸ is, H, methyl, ethyl, isopropyl, cyclopentyl group, a benzyl group, fluorobenzyl group, phenethyl group, selected from thienylmethyl group and thienylethyl group, a compound or a pharmaceutically according to claim 22 Acceptable salt, hydrate or ester. R ⁸ is a phenyl group or a 5-13 membered heteroaryl group, each of which is substituted with 1-4 ^{-Z-R 10} group optionally compound according to claim 22 Or a pharmaceutically acceptable salt, hydrate or ester thereof. R ⁸ is selected from a phenyl group, a 2,3-dihydrobenzo [b] [1,4] dioxinyl group, a thienyl group, a pyridyl group, and an isoxazolyl group, and each of the phenyl group, thienyl group, pyridyl group, and isoxazolyl group is Optionally, 1 to 3 groups independently selected from halogen, —O—Z—R ¹¹ , —NR ¹¹ —ZR ¹² , a C _1-10 alkyl group and a C _1-10 haloalkyl group 23. A compound according to claim 22 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein R ³ and the R ⁸ portion of R ² are attached to them
Together to form a 5- to 12-membered cyclic urea group or a 5- to 12-membered cyclic carbamate group, each of which is optionally substituted with 1 to 4 -ZR ¹⁰ groups. 20. The compound according to any one of claims 9, 12, and 19, or a pharmaceutically acceptable salt, hydrate or ester thereof. R ⁹ is H or methyl group, the compound or a pharmaceutically acceptable salt, hydrate or ester as claimed in claim 26.   The 5- to 12-membered cyclic urea group or the 5- to 12-membered cyclic carbamate group is a 5-membered cyclic urea group, a 6-membered cyclic urea group, a 5-membered cyclic carbamate group, or a 6-membered cyclic carbamate group. Item 26 or 27 or a pharmaceutically acceptable salt, hydrate or ester thereof. (R) -2- (7-methoxycarbonylamino-dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid,
(R) -3-methyl-2- (7- (propoxycarbonylamino) dibenzo [b, d] furan-2-sulfonamido) butanoic acid,
(R) -2- (7- (isopropoxycarbonylamino) dibenzo [b, d] furan-2-sulfonamido) -3-methyl-butanoic acid,
(R) -3-methyl-2- (7- (phenoxycarbonylamino) dibenzo [b, d] furan-2-sulfonamido) butanoic acid,
(R) -2- (7- (3-ethylureido) dibenzo [b, d] furan-2-sulfonamido) -3-methylbutanoic acid,
(R) -2- (7- (3- (4-fluoro-benzyl) -ureido) -dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid,
(R) -2- (7- (3-cyclopentylmethylureido) -dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid,
(R) -2- (7- (3-Isopropylureido) -dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid,
(R) -3-methyl-2- (7- (3- (3,4,5-trimethoxy-phenyl) -ureido) -dibenzofuran-2-sulfonylamino) -butyric acid,
(R) -2- (7- (3- (3,4-difluorophenyl) ureido) dibenzo [b, d] furan-2-sulfonamido) -3-methyl-butanoic acid,
(R) -2- (7- (3- (4- (dimethylamino) phenyl) ureido) dibenzo [b, d] furan-2-sulfonamido) -3-methyl-butanoic acid,
(R) -3-methyl-2- (7- (3- (3-phenoxyphenyl) ureido) dibenzo [b, d] furan-2-sulfonamido) -butanoic acid,
(R) -3-methyl-2- (7-ureidodibenzo [b, d] furan-2-sulfonamido) butanoic acid,
(R) -3-methyl-2- (7- (3- (4- (trifluoromethoxy) phenyl) ureido) dibenzo [b, d] furan-2-sulfonamido) butanoic acid,
(R) -2- (7- (3- (2,6-dichloropyridin-4-yl) ureido) dibenzo [b, d] furan-2-sulfonamido) -3-methyl-butanoic acid,
(R) -3-methyl-2- (7- (3- (2- (thiophen-2-yl) ethyl) ureido) dibenzo [b, d] furan-2-sulfonamido) butanoic acid,
(S) -2- (7- (3-ethylureido) dibenzo [b, d] furan-2-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7-methoxycarbonylamino-dibenzo [b, d] thiophene-2-sulfonamido) -3-methyl-butanoic acid,
(R) -2- (7- (methoxycarbonylamino) dibenzo [b, d] thiophene-2-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8- (isobutoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8-((2-chloroethoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8-((2-bromoethoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8- (isopropoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8-((4-fluorophenoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8-((2-chlorophenoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8- (but-2-ynyloxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-Methyl-2- (8- (p-tolyloxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(S) -3-methyl-2- (8- (phenoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(S) -2- (8- (benzyloxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8- (hexyloxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8-((2-fluoroethoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8- (methoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8- (ethoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-Methyl-2- (8-propoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamidobutanoic acid,
(S) -2- (8- (butoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8-((but-3-ynyloxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8- (3- (3,5-dimethylisoxazol-4-yl) ureido) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-Methyl-2- (8- (3-thiophen-3-ylureido) dibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(S) -3-Methyl-2- (8- (3- (3,4,5-trimethoxyphenyl) ureido) dibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(S) -2- (8- (3- (3,4-difluorophenyl) ureido) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-methyl-2- (8- (3- (3-phenoxyphenyl) ureido) dibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(S) -3-Methyl-2- (8-ureidodibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(S) -2- (8- (3- (2,6-dichloropyridin-4-yl) ureido) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8- (3- (4- (dimethylamino) phenyl) ureido) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-Methyl-2- (8- (3- (2- (thiophen-2-yl) ethyl) ureido) dibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(S) -3-Methyl-2- (8- (3- (4- (trifluoromethoxy) phenyl) ureido) dibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(S) -2- (8- (3-cyclopentylureido) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8- (3- (4-fluorobenzyl) ureido) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8- (methoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(R) -2- (8- (methoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7- (3-cyclopentylureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-Methyl-2- (7- (3- (2- (thiophen-2-yl) ethyl) ureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid,
(S) -2- (7- (3- (4-fluorophenyl) ureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-methyl-2- (7- (3-phenethylureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid,
(S) -2- (7- (3-Benzylureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7- (3- (4-fluorobenzyl) ureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-Methyl-2- (7- (3-p-tolylureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid,
(S) -3-Methyl-2- (7- (3- (3,4,5-trimethoxyphenyl) ureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid,
(S) -2- (7- (3-ethylureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7- (3- (3,4-difluorophenyl) ureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-Methyl-2- (7- (3- (4- (trifluoromethyl) phenyl) ureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid,
(S) -2- (7- (3- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ureido) dibenzo [b, d] thiophene-3-sulfonamide) -3 -Methyl-butanoic acid,
(S) -3-methyl-2- (7- (3-phenylureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid,
(S) -2- (7- (3- (4- (dimethylamino) phenyl) ureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-methyl-2- (7- (3-pyridin-4-ylureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid,
(S) -2- (7- (3- (3,5-dimethylisoxazol-4-yl) ureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7- (methoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7- (ethoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7- (isobutoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (6-Chloro-7- (methoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7- (isopropoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-Methyl-2- (7- (p-tolyloxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid,
(S) -2- (7-((4-fluorophenoxy) carbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-methyl-2- (7- (phenoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid,
(S) -2- (7-((but-3-ynyloxy) carbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-methyl-2- (7-((2- (methylsulfonyl) ethoxy) carbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid,
(S) -2- (7- (benzyloxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-methyl-2- (8- (2-oxooxazolidin-3-yl) dibenzofuran-3-sulfonamido) butanoic acid,
(S) -2- (8- (ethyl (methoxycarbonyl) amino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(R) -3-methyl-2- (7- (2-oxooxazolidin-3-yl) dibenzo [b, d] furan-2-sulfonamido) butanoic acid,
(S) -2- (8-((3-chloropropoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(R) -2- (8-bromo-7- (methoxycarbonylamino) dibenzo [b, d] furan-2-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8-bromo-7- (methoxycarbonylamino) dibenzo [b, d] furan-2-sulfonamido) -3-methyl-butanoic acid,
(S) -3-Methyl-2- (7- (2-oxooxazolidine-3-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(R) -2- (7- (methoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(R) -2- (7- (3- (3,4-difluorophenyl) ureido) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7- (methoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7-((2-fluoroethoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7-((but-2-ynyloxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7-((4-fluorophenoxy) carbonylamino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-Methyl-2- (7- (3-thiophen-3-ylureido) dibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(S) -3-Methyl-2- (7- (3- (2- (thiophen-2-yl) ethyl) ureido) dibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(S) -3-Methyl-2- (7-ureidodibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(S) -2- (7- (3- (3,4-difluorophenyl) ureido) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7- (ethyl (methoxycarbonyl) amino) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-Methyl-2- (8- (2-oxo-1,3-oxazinan-3-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(S) -3-Methyl-2- (7- (2-oxooxazolidine-3-yl) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid,
(S) -2- (7- (methoxycarbonyl (methyl) amino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7- (ethoxycarbonyl (methyl) amino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7- (isopropoxycarbonyl (methyl) amino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7-(((4-fluorophenoxy) carbonyl) (methyl) amino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-methyl-2- (7- (1,3,3-trimethylureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid,
(S) -2- (7- (3-ethyl-1-methylureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7- (3-Benzyl-1-methylureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7- (3-benzyl-1,3-dimethylureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-Methyl-2- (7- (2-oxoimidazolidin-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid,
(S) -3-methyl-2- (7- (2-oxotetrahydropyrimidin-1 (2H) -yl) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid,
(R) -2- (7- (methoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(R) -2- (7- (ethoxycarbonylamino) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(R) -2- (7- (3-cyclopentylureido) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid, or (R) -3-methyl-2- (7- A compound that is (3-phenylureido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid or a pharmaceutically acceptable salt, hydrate or ester thereof. Formula I:
(Where:
R ¹ is an N-linked, free carboxyl or carboxyl-protected, natural or non-natural amino acid, or N-linked amino acid derivative;
R ² is —S (O) R ⁸ or —SO ₂ R ⁸ ;
R ³ is a) H, b) -S (O) _m R ⁸ , c) -S (O) _m OR ⁸ , d) -S (O) _m NR ⁸ R ⁹ , e) -C (O) ^{R 8, f) -C (S} ) OR 8, g) -C (S) R 8, h) -C (S) NR 8 R 9, i) -C (NR 8) NR 8 R 9, j) C _1-10 alkyl group, k) C _2-10 alkenyl group, 1) C _2-10 alkynyl group, m) C _1-10 haloalkyl group, n) C _3-10 cycloalkyl group, o) C _6-14 An aryl group, p) a 3-14 membered cycloheteroalkyl group or q) a 5-13 membered heteroaryl group, wherein each of j) -q) is optionally 1-4- substituted with ^{Z-R 10} group; or ^{R 3,} and ^{R 8} portion of ^{R 2,} they together with the N and S are bound respectively, 3-14 membered Form a cyclic sulfinamide group or 3-14 membered cyclic sulfonamide group, each of which is substituted with 1-4 -Z-R ¹⁰ group optionally;
R ⁴ and R ⁵ are independently a) H, b) —CN, c) —NO ₂ , d) halogen, e) —OR ⁸ , f) —NR ⁸ R ⁹ , g) —S (O _{^{) m R 8, h) -S}} (O) m OR 8, i) -C (O) R 8, j) -C (O) OR 8, k) -C (O) NR 8 R 9, l) ^{-C (S) R 8, m} ) -C (S) OR 8, n) -C (S) NR 8 R 9, o) C 1-10 alkyl _{group, p) C 2-10} alkenyl group, q) C _2-10 alkynyl group, r) C _1-10 haloalkyl group, s) C _3-14 cycloalkyl group, t) C _6-14 aryl group, u) 3-14 membered cycloheteroalkyl group or v) 5 A 13-membered heteroaryl group, wherein each of o) to v) is optionally substituted with 1 to 4 -ZR ¹⁰ groups;
R ⁶ is a) H, b) -S (O) _m R ⁸ , c) -S (O) _m OR ⁸ , d) -C (O) R ⁸ , e) -C (O) OR ⁸ , ^{f) -C (O) NR 8} R 9, g) -C (S) R 8, h) -C (S) OR 8, i) -C (S) NR 8 R 9, j) C 1-10 An alkyl group, k) a C _2-10 alkenyl group, 1) a C _2-10 alkynyl group or m) a C _1-10 haloalkyl group, wherein each of j) -m) is optionally C ₆ Substituted with a _-14 aryl group or a 5-13 membered heteroaryl group, wherein each of the C _6-14 aryl group and the 5-13 membered heteroaryl group is optionally substituted with 1-4 -Z Substituted with -R ¹⁰ groups;
R ⁸ and R ⁹ are independently in each occurrence a) H, b) —OR ¹¹ , c) —SR ¹¹ , d) —S (O) _m R ¹¹ , e) —S (O) _{^{m -OR 11, f) -S (}} O) m -NR 11 R 12, g) -C (O) R 11, h) -C (O) OR 11, i) -C (O) NR 11 R 12 J) —C (S) NR ¹¹ R ¹² , k) C _1-10 alkyl group, 1) C _2-10 alkenyl group, m) C _2-10 alkynyl group, n) C _1-10 alkoxy group, o A) a C _1-10 haloalkyl group, p) a C _3-10 cycloalkyl group, q) a C _6-14 aryl group, r) a 3-14 membered cycloheteroalkyl group or s) a 5-13 membered heteroaryl group. Wherein each of k) to s) is optionally substituted with 1 to 4 —ZR ¹⁰ groups;
R ¹⁰ is, in each occurrence, a) halogen, b) —CN, c) —NO ₂ , d) oxo, e) —O—Z—R ¹¹ , f) —NR ¹¹ —ZR ¹² , g _{^{) -N (O) R 11 -Z}} -R 12, h) -S (O) m R 11, i) -S (O) m O-Z-R 11, j) -S (O) m NR 11 ^{-Z-R 12, k) -C} (O) R 11, l) -C (O) O-Z-R 11, m) -C (O) NR 11 -Z-R 12, n) -C ( S) NR < ¹¹ > -ZR < ¹² >, o) -Si ( _C1-10 alkyl) ₃ , p) _C1-10 alkyl group, q) _C2-10 alkenyl group, r) _C2-10 alkynyl group, _{s) C 1-10} haloalkyl _{group, t) C 3-10} cycloalkyl _{group, u) C 6-14} aryl group, v) 3 to 14 membered cycloheteroalkyl group, or ) A 5 to 13 membered heteroaryl group, wherein each of o) to w) is replaced with 1-4 ^{R 13} groups optionally;
R ¹¹ and R ¹² are independently in each occurrence a) H, b) —OH, c) —SH, d) —S (O) ₂ OH, e) —C (O) OH, f _{) -C (O) NH 2,} g) -C (S) NH 2, h) -S (O) m -C 1-10 _{alkyl, i) -S (O) m} -OC 1-10 alkyl, j ) -OC _1-10 alkyl, k) -C (O) -C _1-10 alkyl, l) -C (O) -OC _1-10 alkyl, m) -C (S) N (C _1-10 alkyl) ) ₂ , n) -C (S) NH-C _1-10 alkyl, o) -C (O) NH-C _1-10 alkyl, p) -C (O) N (C _1-10 alkyl) ₂ , _{q) C 1-10} alkyl _{group, r) C 2-10} alkenyl _{group, s) C 2-10} alkynyl _{group, t) C 1-10} alkoxy _{group, u) C 1-10} Haroaru Le _{group, v) C 3-10} cycloalkyl _{group, w) C 6-14} aryl group, x) 3 to 14 membered cycloheteroalkyl group, or y) 5 to 13 membered heteroaryl group, wherein, each of h) -y) is optionally substituted with 1-4 -R ¹³ groups;
R ¹³ is in each occurrence a) halogen, b) —CN, c) —NO ₂ , d) oxo, e) —OH, f) —NH ₂ , g) —NH (C _1-10 alkyl) , h) _{-N (C 1-10 alkyl) 2, i) -S (O} ) m H, j) -S (O) m -C 1-10 _{alkyl, k) -S (O) 2} OH, l ) -S (O) _m -OC _1-10 alkyl, m) -S (O) _m NH ₂ , n) -S (O) _m NH (C _1-10 alkyl), o) -S (O) _m N (C _1-10 alkyl) ₂ , p) —CHO, q) —C (O) —C _1-10 alkyl, r) —C (O) OH, s) —C (O) —OC _{1-10 alkyl, t) -C (O) NH} 2, u) -C (O) NH-C 1-10 _{alkyl, v) -C (O) N} (C 1-10 _alkyl) 2, _w) -C (S ) NH _{2 , X) -C (S) NH} -C 1-10 _{alkyl, y) -C (S) N} (C 1-10 _{alkyl) 2, z) -Si (C} 1-10 _alkyl) 3, _{aa) C 1 -10} alkyl group, ab) C _2-10 alkenyl group, ac) C _2-10 alkynyl group, ad) C _1-10 alkoxy group, ae) C _1-10 haloalkyl group, af) C _3-10 cycloalkyl group Ag) a C _6-14 aryl group, ah) a 3-14 membered cycloheteroalkyl group or ai) a 5-13 membered heteroaryl group;
X is O, S, S (O), S (O) ₂ or NR ⁶ ;
Y is S (O), S (O) ₂ or C (O);
Z is in each _occurrence a) a divalent C _1-10 alkyl group, b) a divalent C _2-10 alkenyl group, c) a divalent C _2-10 alkynyl group, d) a divalent C _{A 1-10} haloalkyl group or e) a covalent bond; and m is 0, 1 or 2 in each occurrence)
Or a pharmaceutically acceptable salt, hydrate or ester thereof. R ³ is H or -S _(O) m ^{R 8,} a compound or a pharmaceutically acceptable salt, hydrate or ester as claimed in claim 30. R ³ is H or fluoro phenylsulfonyl group, a compound or a pharmaceutically acceptable salt, hydrate or ester as claimed in claim 30. R ² is _-SO 2 ^{R 8,} a compound or a pharmaceutically acceptable salt, hydrate or ester as claimed in any one of claims 30 to 32. R ⁸ is H, C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group, C _1-10 haloalkyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, 3 is selected from the cycloheteroalkyl group, and the 5-13 membered heteroaryl group to 14-membered, _{wherein, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10} haloalkyl Each of the groups, a C _3-10 cycloalkyl group, a C _6-14 aryl group, a 3-14 membered cycloheteroalkyl group and a 5-13 membered heteroaryl group is optionally substituted with 1-4 -Z It is replaced with -R ¹⁰ group, the compound or a pharmaceutically acceptable salt, hydrate or ester as claimed in claim 33. R ⁸ is selected from H, C _1-10 alkyl group, C _6-14 aryl group and 5-13 membered heteroaryl group, wherein C _1-10 alkyl group, C _6-14 aryl group and 5 each of to 13-membered heteroaryl group is substituted with 1-4 -Z-R ¹⁰ group optionally compound according to claim 33 or a pharmaceutically acceptable salt, hydrate Product or ester. R ⁸ is selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a butyl group and a hexyl group, each of which is independently selected from a halogen and a C _1-10 haloalkyl group 34. A compound according to claim 33 or a pharmaceutically acceptable salt, hydrate or ester thereof, optionally substituted with 4 groups. The compound according to claim 33, or a pharmaceutically acceptable salt or hydrate thereof, wherein R ⁸ is selected from a methyl group, an ethyl group, an isopropyl group, a 2-chloromethyl group, and a 2-trifluoromethyl group. Or ester. R ⁸ is selected from phenyl, thienyl and isoxazolyl, each of which is optionally substituted with 1 to 3 groups independently selected from halogen and C _1-10 alkyl groups 34. A compound according to claim 33, or a pharmaceutically acceptable salt, hydrate or ester thereof. R ⁸ is a phenyl group, fluorophenyl group, selected from dimethyl isoxazolyl group and dichloro thienyl group, a compound or a pharmaceutically acceptable salt, hydrate or ester as claimed in claim 33. The R ⁸ portion of R ³ and R ² together with N and S to which they are attached, form a 5-12 membered cyclic sulfinamide group or a 5-12 membered cyclic sulfonamide group. 32. A compound according to claim 30, or a pharmaceutically acceptable salt, hydrate or ester thereof, each of which is optionally substituted with 1 to 4 -ZR ¹⁰ groups.   A 5- to 12-membered cyclic sulfinamide group or a 5- to 12-membered cyclic sulfonamide group is an S-oxoisothiazolidine-2-yl group, an S-oxothiazinan-2-yl group, an S, S-dioxoisothiazolidine- 41. A compound according to claim 40 which is a 2-yl group or a S, S-dioxothiazinan-2-yl group. (R) -3-methyl-2- (7- (methylsulfonamido) dibenzo [b, d] furan-2-sulfonamido) butanoic acid,
(S) -3-Methyl-2- (7- (methylsulfonamido) dibenzo [b, d] furan-2-sulfonamido) butanoic acid,
(R) -2- (7- (chloromethylsulfonamido) dibenzo [b, d] furan-2-sulfonamido) -3-methyl-butanoic acid,
(R) -3-methyl-2- (7- (1-methylethylsulfonamido) dibenzo [b, d] furan-2-sulfonamido) butanoic acid,
(R) -2- (7- (3,5-dimethylisoxazol-4-yl-sulfonamido) dibenzo [b, d] furan-2-sulfonamido) -3-methyl-butanoic acid,
(R) -3-methyl-2- (7- (phenylsulfonamido) dibenzo [b, d] furan-2-sulfonamido) butanoic acid,
(S) -3-methyl-2- (7- (methylsulfonamido) dibenzo [b, d] thiophene-2-sulfonamido) butanoic acid,
(R) -3-methyl-2- (7- (methylsulfonamido) dibenzo [b, d] thiophene-2-sulfonamido) butanoic acid,
(S) -3-methyl-2- (8- (methylsulfonamido) -dibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(S) -3-methyl-2- (8- (methylsulfonamido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid,
(R) -3-methyl-2- (8- (methylsulfonamido) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid,
(S) -3-Methyl-2- (8- (2,2,2-trifluoroethylsulfonamido) dibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(S) -2- (8- (4-Fluoro-N- (4-trifluorophenylsulfonyl) phenylsulfonamido) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8- (4,5-dichlorothiophene-2-sulfonamido) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
N-{[7- (1,1-dioxideisothiazolidin-2-yl) dibenzo [b, d] thien-3-yl] sulfonyl} -L-valine, or N-{[7- (1-oxide A compound that is isothiazolidin-2-yl) dibenzo [b, d] thien-3-yl] sulfonyl} -L-valine or a pharmaceutically acceptable salt, hydrate or ester thereof. Formula I:
(Where:
R ¹ is an N-linked, free carboxyl or carboxyl-protected, natural or non-natural amino acid, or N-linked amino acid derivative;
R ² and R ³ together with their common nitrogen atom form a) a 3-14 membered cycloheteroalkyl group or b) a 5-13 membered heteroaryl group, wherein a) And each of b) is optionally substituted with 1 to 4 -ZR ¹⁰ groups;
However, a 3-14 membered cycloheteroalkyl group is a 3-14 membered cyclic urea group, a 3-14 membered cyclic carbamate group, a 3-14 membered cyclic sulfinamide group, or a 3-14 membered cyclic sulfonamide group. not;
R ⁴ and R ⁵ are independently a) H, b) —CN, c) —NO ₂ , d) halogen, e) —OR ⁸ , f) —NR ⁸ R ⁹ , g) —S (O _{^{) m R 8, h) -S}} (O) m OR 8, i) -C (O) R 8, j) -C (O) OR 8, k) -C (O) NR 8 R 9, l) ^{-C (S) R 8, m} ) -C (S) OR 8, n) -C (S) NR 8 R 9, o) C 1-10 alkyl _{group, p) C 2-10} alkenyl group, q) C _2-10 alkynyl group, r) C _1-10 haloalkyl group, s) C _3-14 cycloalkyl group, t) C _6-14 aryl group, u) 3-14 membered cycloheteroalkyl group or v) 5 A 13-membered heteroaryl group, wherein each of o) to v) is optionally substituted with 1 to 4 -ZR ¹⁰ groups;
R ⁶ is a) H, b) -S (O) _m R ⁸ , c) -S (O) _m OR ⁸ , d) -C (O) R ⁸ , e) -C (O) OR ⁸ , ^{f) -C (O) NR 8} R 9, g) -C (S) R 8, h) -C (S) OR 8, i) -C (S) NR 8 R 9, j) C 1-10 An alkyl group, k) a C _2-10 alkenyl group, 1) a C _2-10 alkynyl group or m) a C _1-10 haloalkyl group, wherein each of j) -m) is optionally C ₆ Substituted with a _-14 aryl group or a 5-13 membered heteroaryl group, wherein each of the C _6-14 aryl group and the 5-13 membered heteroaryl group is optionally substituted with 1-4 -Z Substituted with -R ¹⁰ groups;
R ⁸ and R ⁹ are independently in each occurrence a) H, b) —OR ¹¹ , c) —SR ¹¹ , d) —S (O) _m R ¹¹ , e) —S (O) _{^{m -OR 11, f) -S (}} O) m -NR 11 R 12, g) -C (O) R 11, h) -C (O) OR 11, i) -C (O) NR 11 R 12 J) —C (S) NR ¹¹ R ¹² , k) C _1-10 alkyl group, 1) C _2-10 alkenyl group, m) C _2-10 alkynyl group, n) C _1-10 alkoxy group, o A) a C _1-10 haloalkyl group, p) a C _3-10 cycloalkyl group, q) a C _6-14 aryl group, r) a 3-14 membered cycloheteroalkyl group or s) a 5-13 membered heteroaryl group. Wherein each of k) to s) is optionally substituted with 1 to 4 —ZR ¹⁰ groups;
R ¹⁰ is, in each occurrence, a) halogen, b) —CN, c) —NO ₂ , d) oxo, e) —O—Z—R ¹¹ , f) —NR ¹¹ —ZR ¹² , g _{^{) -N (O) R 11 -Z}} -R 12, h) -S (O) m R 11, i) -S (O) m O-Z-R 11, j) -S (O) m NR 11 ^{-Z-R 12, k) -C} (O) R 11, l) -C (O) O-Z-R 11, m) -C (O) NR 11 -Z-R 12, n) -C ( S) NR < ¹¹ > -ZR < ¹² >, o) -Si ( _C1-10 alkyl) ₃ , p) _C1-10 alkyl group, q) _C2-10 alkenyl group, r) _C2-10 alkynyl group, _{s) C 1-10} haloalkyl _{group, t) C 3-10} cycloalkyl _{group, u) C 6-14} aryl group, v) 3 to 14 membered cycloheteroalkyl group, or ) A 5 to 13 membered heteroaryl group, wherein each of o) to w) is replaced with 1-4 ^{R 13} groups optionally;
R ¹¹ and R ¹² are independently in each occurrence a) H, b) —OH, c) —SH, d) —S (O) ₂ OH, e) —C (O) OH, f _{) -C (O) NH 2,} g) -C (S) NH 2, h) -S (O) m -C 1-10 _{alkyl, i) -S (O) m} -OC 1-10 alkyl, j ) -OC _1-10 alkyl, k) -C (O) -C _1-10 alkyl, l) -C (O) -OC _1-10 alkyl, m) -C (S) N (C _1-10 alkyl) ) ₂ , n) -C (S) NH-C _1-10 alkyl, o) -C (O) NH-C _1-10 alkyl, p) -C (O) N (C _1-10 alkyl) ₂ , _{q) C 1-10} alkyl _{group, r) C 2-10} alkenyl _{group, s) C 2-10} alkynyl _{group, t) C 1-10} alkoxy _{group, u) C 1-10} Haroaru Le _{group, v) C 3-10} cycloalkyl _{group, w) C 6-14} aryl group, x) 3 to 14 membered cycloheteroalkyl group, or y) 5 to 13 membered heteroaryl group, wherein, each of h) -y) is optionally substituted with 1-4 -R ¹³ groups;
R ¹³ is in each occurrence a) halogen, b) —CN, c) —NO ₂ , d) oxo, e) —OH, f) —NH ₂ , g) —NH (C _1-10 alkyl) , h) _{-N (C 1-10 alkyl) 2, i) -S (O} ) m H, j) -S (O) m -C 1-10 _{alkyl, k) -S (O) 2} OH, l ) -S (O) _m -OC _1-10 alkyl, m) -S (O) _m NH ₂ , n) -S (O) _m NH (C _1-10 alkyl), o) -S (O) _m N (C _1-10 alkyl) ₂ , p) —CHO, q) —C (O) —C _1-10 alkyl, r) —C (O) OH, s) —C (O) —OC _{1-10 alkyl, t) -C (O) NH} 2, u) -C (O) NH-C 1-10 _{alkyl, v) -C (O) N} (C 1-10 _alkyl) 2, _w) -C (S ) NH _{2 , X) -C (S) NH} -C 1-10 _{alkyl, y) -C (S) N} (C 1-10 _{alkyl) 2, z) -Si (C} 1-10 _alkyl) 3, _{aa) C 1 -10} alkyl group, ab) C _2-10 alkenyl group, ac) C _2-10 alkynyl group, ad) C _1-10 alkoxy group, ae) C _1-10 haloalkyl group, af) C _3-10 cycloalkyl group Ag) a C _6-14 aryl group, ah) a 3-14 membered cycloheteroalkyl group or ai) a 5-13 membered heteroaryl group;
X is O, S, S (O), S (O) ₂ or NR ⁶ ;
Y is S (O), S (O) ₂ or C (O);
Z is in each _occurrence a) a divalent C _1-10 alkyl group, b) a divalent C _2-10 alkenyl group, c) a divalent C _2-10 alkynyl group, d) a divalent C _{A 1-10} haloalkyl group or e) a covalent bond; and m is 0, 1 or 2 in each occurrence)
Or a pharmaceutically acceptable salt, hydrate or ester thereof. R ² and R ³ together with their common nitrogen atom form a 5 or 6 membered cycloheteroalkyl group optionally substituted with 1 to 4 —Z—R ¹⁰ groups 45. The compound of claim 43, or a pharmaceutically acceptable salt, hydrate or ester thereof.   The 5- or 6-membered cycloheteroalkyl group is selected from a pyrrolidinyl group, an oxazolinyl group, a thiazolinyl group, an isothiazolinyl group, an imidazolinyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, a thiomorpholinyl group and a 1,3-oxadinanyl group, Item 44. A pharmaceutically acceptable salt, hydrate or ester thereof, -Z-R ¹⁰ is halogen, is selected from oxo and C _1-6 alkyl group, a compound or a pharmaceutically acceptable salt, hydrate or ester as claimed in claim 44. R ² and R ³ together with their common nitrogen atom form a 5- or 6-membered heteroaryl group optionally substituted with 1 to 4 —Z—R ¹⁰ groups. 45. A compound according to claim 43, or a pharmaceutically acceptable salt, hydrate or ester thereof.   48. The compound according to claim 47, or a pharmaceutically acceptable salt, hydrate, or thereof, wherein the 5- or 6-membered heteroaryl group is selected from a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, and a tetrazolyl group. ester. 48. The compound according to claim 47 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein Z is selected from a divalent _C1-4 alkyl group and a covalent bond. R ¹⁰ is —CN, —O—Z—R ¹¹ , —NR ¹¹ —Z—R ¹² , —C (O) O—Z—R ¹¹ , —C (O) NR ¹¹ —Z—R ¹² , — Selected from Si (C _1-10 alkyl) ₃ , C _1-10 alkyl group, C _1-10 haloalkyl group, C _3-10 cycloalkyl group, C _6-14 aryl group and 5-13 membered heteroaryl group Wherein each of the C _1-10 alkyl group, the C _3-10 cycloalkyl group, the C _6-14 aryl group and the 5-13 membered heteroaryl group is optionally substituted with 1 to 4 R ¹³ groups. 48. The compound of claim 47, or a pharmaceutically acceptable salt, hydrate or ester thereof, substituted with (R) -2- (7- (4- (2-hydroxy-ethyl)-(1,2,3) triazol-1-yl) dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid,
(R) -2- (7- (4-isobutyl- (1,2,3) triazol-1-yl) -dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid,
(R) -2- (7- (4-hydroxymethyl- (1,2,3) triazol-1-yl) -dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid,
(R) -2- (7- (4-cyclohexyl- (1,2,3) triazol-1-yl) -dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid,
(R) -1- (8- (1-carboxy-2-methyl-propylsulfamoyl) -dibenzofuran-3-yl) -1H- (1,2,3) -triazole-4-carboxylic acid,
(R) -3-methyl-2- (7- (4-phenyl- (1,2,3) triazol-1-yl) -dibenzofuran-2-sulfonylamino) -butyric acid,
(R) -2- (7- (4-Dimethylaminomethyl- (1,2,3) triazol-1-yl) -dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid,
(S) -3-Methyl-2- (8-morpholinodibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(S) -3-methyl-2- (8- (3- (trifluoromethyl) -1H-pyrazol-1-yl) dibenzofuran-3-sulfonamido) butanoic acid,
(S) -2- (8- (1H-pyrazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-Methyl-2- (8- (piperazin-1-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(S) -2- (8- (1H-imidazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8- (4,5-dimethyl-1H-imidazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(R) -3-Methyl-2- (7- (4-((trimethylsilyl) methyl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] furan-2-sulfonamide) Butanoic acid,
(S) -2- (8- (4-cyclohexyl-1H-1,2,3-triazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8- (4- (2-hydroxyethyl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methyl -Butanoic acid,
(S) -2- (8- (4-((Dimethylamino) methyl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3- Methyl-butanoic acid,
(S) -3-Methyl-2- (8- (4-phenyl-1H-1,2,3-triazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(S) -2- (8- (4-Isobutyl-1H-1,2,3-triazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-Methyl-2- (7- (4- (1-methyl-1H-pyrrol-2-yl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] Thiophene-3-sulfonamido) butanoic acid,
(S) -3-Methyl-2- (7- (4-phenyl-1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) butanoic acid,
(S) -2- (7- (4-cyclohexyl-1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7- (4- (methoxymethyl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butane acid,
(S) -2- (7- (4-tert-butyl-1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid ,
(S) -2- (7- (4-((Dimethylamino) methyl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) -3- Methyl-butanoic acid,
(S) -2- (7- (4- (hydroxymethyl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butane acid,
(S) -2- (7- (4- (methoxycarbonyl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butane acid,
(S) -1- (7- (N- (1-carboxy-2-methylpropyl) sulfamoyl) dibenzo [b, d] thiophen-3-yl) -1H-1,2,3-triazole-4-carboxylic acid acid,
(S) -2- (7- (4-Cyano-1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7- (4-Isopropyl-1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7- (4-carbamoyl-1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7- (4- (furan-2-yl) -1H-1,2,3-triazol-1-yl) dibenzo [b, d] thiophene-3-sulfonamido) -3- Methyl-butanoic acid,
(R) -2- (7- (4H-1,2,4-triazol-4-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methyl-butanoic acid,
(R) -2- (7- (2,5-dimethyl-1H-pyrrol-1-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methyl-butanoic acid,
(S) -3-Methyl-2- (8- (3- (4-nitrophenyl) -1H-pyrazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(R) -2- (7- (1H-pyrrol-1-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7- (1H-pyrrol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (7- (2,5-dimethyl-1H-pyrrol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-methyl-2- (7- (3- (trifluoromethyl) -1H-pyrazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(S) -3-Methyl-2- (8- (4-methylpiperazin-1-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(S) -2- (8- (1H-1,2,4-triazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -2- (8- (4,4-difluoropiperidin-1-yl) dibenzo [b, d] furan-3-sulfonamido) -3-methyl-butanoic acid,
(S) -3-methyl-2- (8- (4-methyl-1H-imidazol-1-yl) dibenzo [b, d] furan-3-sulfonamido) butanoic acid,
(R) -2- (7- (5-methoxy-2H-tetrazol-2-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methyl-butanoic acid,
(R) -2- (7- (5-hydroxy-2H-tetrazol-2-yl) dibenzo [b, d] furan-2-sulfonamido) -3-methyl-butanoic acid, or N-{[7- A compound which is (1,1-dioxidethiomorpholinemorpholin-4-yl) dibenzo [b, d] thien-3-yl] sulfonyl} -L-valine or a pharmaceutically acceptable salt, hydrate or ester. The compound of formula I is
51. The compound according to any one of claims 1 to 7, 9 to 28, 30 to 41 and 43 to 50, or a pharmaceutically acceptable salt, hydrate or ester thereof, selected from: 53. A compound according to claim 52 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein R < ⁴ > and R < ⁵ > are independently selected from H and halogen. R ⁴ is H, R ⁵ is H, it is selected from Cl and Br, the compound or a pharmaceutically acceptable salt, hydrate or ester as claimed in claim 52.   55. A compound according to any of claims 52 to 54 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein X is O.   55. A compound according to any of claims 52 to 54 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein X is S. 57. A compound according to any one of claims 52 to 56 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein Y is S (O) ₂ . R ¹ is W—V—NH—
here:
W _{^{is, a) -C (O) R}} 14, b) -S (O) m R 14, c) -S (O) m OR 14, d) -S (O) m NR 14 R 15, e) ^{-C (O) OR 14, f} ) -C (O) NR 14 R 15, g) -C (S) R 14, h) -C (S) OR 14, i) -NR 14 R 15, j) be ^{-C (NR 14) NR 14 R} 15, k) -P (O) (oR 14) 2 or _{^{l) -B (oR 14) 2}} ;
V is a) -CR ¹⁴ R ^16- , b) -CH ₂ CR ¹⁴ R ^16- , c)-(CH = CR ¹⁴ R ¹⁶ )-or d) -BHR ^16- ;
R ¹⁴ and R ¹⁵ are independently in each occurrence a) H, b) —OH, c) —SH, d) —S (O) ₂ OH, e) —C (O) OH, f _{) -C (O) NH 2,} g) -C (S) NH 2, h) -S (O) m -C 1-10 _{alkyl, i) -S (O) m} -OC 1-10 alkyl, j ) -C (O) -C _1-10 alkyl, k) -C (O) -OC _1-10 alkyl, l) -C (O) NH-C _1-10 alkyl, m) -C (O) N (C _1-10 alkyl) ₂ , n) —C (S) NH—C _1-10 alkyl, o) —C (S) N (C _1-10 alkyl) ₂ , p) C _1-10 alkyl group, _{q) C 2-10} alkenyl _{group, r) C 2-10} alkynyl _{group, s) C 1-10} alkoxy _{groups, t) C 1-10} haloalkyl _{group, u) C 3-10} cycloalkyl Alkyl _{group, v)} a _{C 6-14} aryl group, w) 3 to 14 membered cycloheteroalkyl group, or x) 5 to 13 membered heteroaryl group, _{wherein, C 1-10} alkyl _{group, C 2- A 10} alkenyl group, a C _2-10 alkynyl group, a C _1-10 alkoxy group, a C _1-10 haloalkyl group, a C _3-10 cycloalkyl group, a C _6-14 aryl group, a 3-14 membered cycloheteroalkyl group and each of 5-13 membered heteroaryl groups are substituted with 1-4 ^{R 17} groups optionally;
R ¹⁶ is independently H or the side chain of a natural or non-natural amino acid; and R ¹⁷ is independently in each occurrence a) halogen, b) —CN, c) —NO _2. D) oxo, e) —OH, f) —NH ₂ , g) —NH (C _1-10 alkyl), h) —N (C _1-10 alkyl) ₂ , i) —S (O) _m H _{, j) -S (O) m} -C 1-10 _{alkyl, k) -S (O) 2} OH, l) -S (O) m -OC 1-10 _{alkyl, m) -S (O) m} NH _{2, n) -S (O)} m NH (C 1-10 _{alkyl), o) -S (O)} m n (C 1-10 _{alkyl) 2, p) -CHO, q} ) -C (O) - C _1-10 alkyl, r) -C (O) OH , s) -C (O) -OC 1-10 _{alkyl, t) -C (O) NH} 2, u) -C (O) NH C _{1-10 alkyl, v) -C (O) N} (C 1-10 _{alkyl) 2, w) -C (S} ) NH 2, x) -C (S) NH-C 1-10 alkyl, y) -C _{(S) N (C 1-10 alkyl) 2, z) -Si (C} 1-10 _alkyl) 3, _{aa) C 1-10} alkyl group, _{ab) C 2-10} alkenyl group, ac) _{C 2 -10} alkynyl group, ad) C _1-10 alkoxy group, ae) C _1-10 haloalkyl group, af) C _3-10 cycloalkyl group, ag) C _6-14 aryl group, ah) 3-14 membered cyclo A heteroalkyl group or ai) a 5- to 13-membered heteroaryl group,
58. A compound according to any of claims 52 to 57 or a pharmaceutically acceptable salt, hydrate or ester thereof. W is, -C (O) a ^{OR 14,} V ^{is, -CR} 14 ^{R 16} - is a compound or a pharmaceutically acceptable salt, hydrate or ester as claimed in claim 58. R ¹ is N-linked, is free carboxyl or carboxyl protecting natural or unnatural D- alpha - an amino acid compound according to any one of claims 52 to 59 or a pharmaceutically acceptable Salt, hydrate or ester. R ¹ is N-linked, is free carboxyl or carboxyl protecting natural or unnatural L- alpha - an amino acid compound according to any one of claims 52 to 59 or a pharmaceutically acceptable Salt, hydrate or ester.   62. The compound according to any one of claims 52 to 61, or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein the N-linked amino acid derivative is obtained from a natural amino acid. R ¹⁶ is an isopropyl group, a compound or a pharmaceutically acceptable salt, hydrate or ester as claimed in claim 58 or 59. R ¹ is a N-linked valine, compound, or a pharmaceutically acceptable salt, hydrate or ester as claimed in any one of claims 52 to 63. R ¹ is a N-linked D- valine, compound, or a pharmaceutically acceptable salt, hydrate or ester as claimed in any one of claims 52-60 and 62-64.   66. A pharmaceutical composition comprising a compound according to any of claims 1 to 65 or a pharmaceutically acceptable salt, hydrate or ester thereof and a pharmaceutically acceptable carrier or excipient.   66. A method of treating or inhibiting a pathological condition or disorder mediated in whole or in part by a matrix metalloprotease in a mammal, comprising an effective amount of one or more of claims 1-65. Or administering a pharmaceutically acceptable salt, hydrate or ester thereof to the mammal.   68. The method of claim 67, wherein the matrix metalloprotease is MMP-12.   69. The pathological condition or disorder is selected from osteoarthritis, rheumatoid arthritis, atherosclerosis, heart failure, fibrosis, emphysema, tumor growth, asthma and chronic obstructive pulmonary disorder. The method described in 1.   70. The method of claim 69, wherein the mammal is a human.